Systems and Methods for Treating an Opioid-Induced Adverse Pharmacodynamic Response

ABSTRACT

Disclosed in certain embodiments is a method of treating or preventing an opioid-induced adverse pharmacodynamic response comprising administering to a patient in need thereof an effective amount of buprenorphine.

FIELD OF THE INVENTION

The invention is directed to systems and methods to treat or prevent anopioid-induced adverse pharmacodynamic response.

BACKGROUND OF THE INVENTION

Endogenous opioids are found throughout the body and are involved in avariety of homeostatic functions and movement control. Receptors thatare regulated by endogenous opioids include delta (δ) receptors, kappa(κ) receptors and mu (μ) receptors, all of which are located in thebrain and the peripheral nervous system and play a role in analgesia. Ofthese receptors, the mu (μ) receptors are located in the humangastrointestinal tract on myenteric and submucosal neurons and on immunecells of the lamina propria and play a role in gastrointestinalfunction.

Exogenous opioids, such as morphine, oxycodone, hydrocodone,buprenorphine and fentanyl, are commonly prescribed to treat both acuteand chronic pain, as their action on the opioid receptors can provideeffective analgesia. However, with respect to the mu (μ) receptors, thestimulating effect exogenous opioids have on these receptors may alsocause an adverse pharmacodynamic response including bowel dysfunctionthat can be manifested by, e.g., decreased gastric motility, delayedgastric emptying, constipation, bloating and cramping. Other adversepharmacodynamic responses associated with opioid therapy include nausea,vomiting, somnolence, dizziness, respiratory depression, headache, drymouth, sedation, sweats, asthenia, hypotension, dysphoria, delirium,miosis, pruritis, urticaria, urinary retention, hyperalgesia, allodynia,physical dependence and tolerance.

Opioid-induced adverse pharmacodynamic responses in patients receivingopioid therapy for pain management can be particularly troublesome, asthese patients are already trying to manage severe pain, and the addeddiscomfort of adverse side effects can add to their distress. In somecases, the side effects may be so extreme that the patient would ratherdiscontinue use of the opioid than continue to suffer with such sideeffects.

In the case of opioid-induced bowel dysfunction, current treatmentsinclude administration of laxatives, opioid antagonists and prokineticagents. However, all of these treatments are not without risk.Laxatives, such as bisacodyl and psyllium, have a long history of safetyand efficacy issues, and can themselves produce severe side effects suchas dehydration and bowel obstruction Opioid antagonists, such asnaloxone and naltrexone, while acting to suppress the receptors causingthe bowel dysfunction, can reverse the desired analgesic effect of theopioid. Prokinetic agents, such as metoclopramide, may improvegastrointestinal motility but are associated with extrapyramidaleffects, such as acute dystonic reactions, pseudoparkinsonism orakathisia.

There remains a need in the art for a composition and method to preventor treat an opioid-induced adverse pharmacodynamic response thatminimizes the issues of the current treatment protocols

All references cited herein are incorporated by reference in theirentireties for all purposes.

OBJECTS AND SUMMARY

It is an object of certain embodiments of the invention to providemethods of treating or preventing an opioid-induced adversepharmacodynamic response.

It is an object of certain embodiments of the invention to providemethods of treating or preventing an opioid-induced adversepharmacodynamic response in a patient on chronic opioid therapy.

It is an object of certain embodiments of the invention to providemethods of treating or preventing an opioid-induced adversepharmacodynamic response in an opioid naive patient.

It is an object of certain embodiments of the invention to providemethods of treating or preventing an opioid-induced adversepharmacodynamic response resulting from administration of an opioidhaving an E_(max) of greater than about 25%.

It is an object of certain embodiments of the invention to providemethods of treating or preventing an opioid-induced adversepharmacodynamic response comprising administering buprenorphine to apatient in need thereof.

It is an object of certain embodiments of the invention to providepharmaceutical compositions for treating or preventing an opioid-inducedadverse pharmacodynamic response.

It is an object of certain embodiments of the invention to providepharmaceutical compositions for treating or preventing an opioid-inducedadverse pharmacodynamic response in a patient on chronic opioid therapy.

It is an object of certain embodiments of the invention to providepharmaceutical compositions for treating or preventing an opioid-inducedadverse pharmacodynamic response in an opioid naive patient.

It is an object of certain embodiments of the invention to providepharmaceutical compositions for treating or preventing an opioid-inducedadverse pharmacodynamic response resulting from administration of anopioid having an E_(max) of greater than about 25%.

It is an object of certain embodiments of the invention to providepharmaceutical compositions comprising buprenorphine for treating orpreventing an opioid-induced adverse pharmacodynamic response in apatient in need thereof.

It is an object of certain embodiments of the invention to providemethods of preparing the pharmaceutical compositions disclosed hereinfor treating or preventing an opioid-induced adverse pharmacodynamicresponse in a patient in need thereof.

It is an object of certain embodiments of the invention to provide kitsfor preventing for treating or preventing an opioid-induced adversepharmacodynamic response in a patient in need thereof.

The above objects of the present invention and others can be achieved bythe present invention, which in certain embodiments is directed to amethod of treating or preventing an opioid-induced adversepharmacodynamic response comprising administering to a patient in needthereof, an effective amount of buprenorphine to treat or prevent anopioid-induced adverse pharmacodynamic response.

In certain embodiments, the present invention is directed to a method oftreating or preventing an opioid-induced adverse pharmacodynamicresponse comprising administering to a patient on chronic administrationof an opioid having an E_(max) of greater than about 25%, an effectiveamount of buprenorphine to treat or prevent the opioid-induced adversepharmacodynamic response.

In certain embodiments, the present invention is directed to a method oftreating or preventing an opioid-induced adverse pharmacodynamicresponse comprising administering to an opioid naive patient an opioidhaving an E_(max) of greater than about 25%, and an effective amount ofbuprenorphine to treat the opioid-induced adverse pharmacodynamicresponse.

In certain embodiments, the present invention is directed to a method oftreating or preventing an opioid-induced adverse pharmacodynamicresponse comprising concurrently administering to a patient in needthereof (i) an effective amount of buprenorphine to treat or prevent anopioid-induced adverse pharmacodynamic response and (ii) another opioid.

In certain embodiments, the present invention is directed to a kitcomprising (i) a unit dose of an effective amount of buprenorphine toprevent or treat an opioid-induced adverse pharmacodynamic responseinduced by another opioid and (ii) a unit dose of another opioid in aneffective amount to treat pain, diarrhea, cough or anxiety.

In describing the present invention, the following terms are to be usedas indicated below. As used herein, the singular forms “a,” “an,” and“the” include plural references unless the context clearly indicatesotherwise. Thus, for example, reference to “an opioid” includes a singleopioid as well as a mixture of two or more different opioids.

As used herein, the term “therapeutically effective” refers to theamount of drug or the rate of drug administration needed to produce adesired therapeutic result.

As used herein, the term “prophylactically effective” refers to theamount of drug or the rate of drug administration needed to produce adesired preventive result.

The term “patient” means a subject, particularly a human, who haspresented a clinical manifestation of a particular symptom or symptomssuggesting the need for treatment, who is treated preventatively orprophylactically for a condition, or who has been diagnosed with acondition to be treated. The term “subject” is inclusive of thedefinition of the term “patient” and does not exclude individuals whoare entirely normal in all respects or with respect to a particularcondition.

As used here, the term “patient in need thereof” refers to a patientexperiencing an opioid-induced adverse pharmacodynamic response such as,but not limited to, bowel dysfunction, nausea, vomiting, somnolence,dizziness, respiratory depression, headache, dry mouth, sedation,sweats, asthenia, hypotension, dysphoria, delirium, miosis, pruritis,urticaria, urinary retention, hyperalgesia, allodynia, physicaldependence or tolerance.

“Pharmaceutically acceptable salts” include, but are not limited to,inorganic acid salts such as hydrochloride, hydrobromide, sulfate,phosphate and the like; organic acid salts such as formate, acetate,trifluoroacetate, maleate, tartrate and the like; sulfonates such asmethanesulfonate, benzenesulfonate, p-toluenesulfonate and the like;amino acid salts such as arginate, asparaginate, glutamate and the like;metal salts such as sodium salt, potassium salt, cesium salt and thelike; alkaline earth metals such as calcium salt, magnesium salt and thelike; and organic amine salts such as triethylamine salt, pyridine salt,picoline salt, ethanolamine salt, triethanolamine salt,discyclohexylamine salt, N,N′-dibenzylethylenediamine salt and the like.

The term “buprenorphine” means buprenorphine free base, and allpharmaceutically acceptable salts, complexes, crystalline forms,co-crystals, hydrates, solvates, and mixtures thereof. In certainembodiments, the buprenorphine utilized in the present invention isbuprenorphine base or a pharmaceutically acceptable salt thereof.

The term “C_(max)” denotes the maximum plasma concentration obtainedduring a dosing interval.

The term “bioavailability” is defined for purposes of the presentinvention as the relevant extent to which the drug (e.g., oxycodone) isabsorbed from the unit dosage forms. Bioavailability is also referred toas AUC (i.e., area under the plasma concentration/time curve).

The term “opioid-induced bowel dysfunction” means a symptom associatedwith the digestive system, including the gastrointestinal tract causedor exacerbated by an opioid. The symptoms include but are not limited toconstipation, decreased gastric emptying, abdominal cramping, spasm,bloating, delayed gastro-intestinal transit and the formation of harddry stools.

The term “opioid analgesic” means any material that produces ananalgesic effect through modulation of an opioid receptor, whether ornot approved by a government agency for that purpose. The term includesall pharmaceutically active forms of the opioid analgesic, including thefree base form of the agent, and all pharmaceutically acceptable salts,complexes, crystalline forms, co-crystals, hydrates, solvates, andmixtures thereof, where the form is pharmaceutically active.

The term “opioid-induced adverse pharmacodynamic response” means anunintended side effect experienced by a patient receiving opioid therapyfor an intended therapeutic effect. Typically, the intended affect isanalgesia. The intended effect can also be the treatment of diarrhea,cough, anxiety (e.g., due to shortness of breath) and opioid dependence.Unintended side effects associated with opioid therapy include boweldysfunction, nausea, vomiting, somnolence, dizziness, respiratorydepression, headache, dry mouth, sedation, sweats, asthenia,hypotension, dysphoria, delirium, miosis, pruritis, urticaria, urinaryretention, hyperalgesia, allodynia, physical dependence and tolerance.

The term “peripherally restricted opioid-induced adverse pharmacodynamicresponse” means a non-central nervous system-mediated unintended sideeffect (e.g., bowel dysfunction) experienced by a patient receivingperipheral opioid therapy for an intended therapeutic effect (e.g.,analgesia).

The term “peripherally restricted opioid analgesic” means any materialthat produces an analgesic effect through modulation of a peripheralopioid receptor (whether or not approved by a government agency for thatpurpose) and does not cross or significantly cross the blood brainbarrier. The term includes all pharmaceutically active forms of theperipherally restricted opioid analgesic, including the free base formof the agent, and all pharmaceutically acceptable salts, complexes,crystalline forms, co-crystals, hydrates, solvates, and mixturesthereof, where the form is pharmaceutically active.

The term “concurrently” means that a dose of one agent is administeredprior to the end of the dosing interval of another agent. For example, adose of an opioid analgesic with a 12-hour dosing interval would beconcurrently administered with a buprenorphine dose administered within12 hours of the opioid administration.

The term “E_(max)” means the maximal μ GTP effect elicited by a compoundrelative (expressed as a %) to the effect elicited by [D-Ala²,N-methyl-Phe⁴, Gly-ol⁵]-enkephalin (a/k/a DAMGO), which is a μ agoniststandard. Generally, the E_(max) value measures the efficacy of acompound to treat or prevent pain or diarrhea.

The term “opioid naive” refers to patients who are not receiving opioidanalgesics on a daily basis

The term “opioid tolerant” means patients who are chronically receivingopioid analgesics on a daily basis.

The term “first administration” means a single dose at the initiation oftherapy to an individual subject, patient, or healthy subject or asubject population, patient population, or healthy subject population.

The term “steady state” means that the amount of the drug reaching thesystem is approximately the same as the amount of the drug leaving thesystem. Thus, at “steady-state”, the patient's body eliminates the drugat approximately the same rate that the drug becomes available to thepatient's system through absorption into the blood stream.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A and 1B are graphical depictions of the results of Example 1.

FIGS. 2A and 2B are graphical depictions of the results of Example 2.

FIGS. 3A and 3B are graphical depictions of the results of Example 3.

FIGS. 4A and 4B are graphical depictions of the results of Example 4.

FIGS. 5A, 5B and 5C are graphical depictions of the results of Example5.

FIGS. 6A, 6B and 6C are graphical depictions of the results of Example6.

FIGS. 7A, 7B, 7C and 7D are graphical depictions of the results ofExample 7.

FIGS. 8A, 8B, 8C and 8D are graphical depictions of the results ofExample 8.

FIGS. 9A, 9B and 9C are graphical depictions of the results of Example9.

FIG. 10 is a graphical depiction of the results of Example 10.

FIG. 11 is a graphical depiction of the results of Example 11.

FIGS. 12A and 12B are graphical depictions of the results of Example 12.

FIGS. 13A and 13B are graphical depictions of the results of Example 13.

FIGS. 14A and 14B are graphical depictions of the results of Example 14.

FIG. 15 is a graphical depiction of the results of Example 15.

FIG. 16 is a graphical depiction of the results of Example 16.

FIGS. 17A and 17B are graphical depictions of the results of Example 17.

FIGS. 18A and 18B are graphical depictions of the results of Example 18.

FIGS. 19A and 19B are graphical depictions of the results of Example 19.

FIG. 20 is a graphical depiction of the results of Example 20.

FIG. 21 is a graphical depiction of the results of Example 21.

FIG. 22 is graphical depiction of the results of Example 22.

FIG. 23 is a graphical depiction of the results of Example 23.

FIG. 24 is a graphical depiction of the results of Example 24.

DETAILED DESCRIPTION

Buprenorphine is commonly used for its analgesic properties and isformulated, e.g., in a transdermal patch (Butrans® buprenorphinetransdermal system) to provide 5 mcg/hour, 10 mcg/hour or 20 mcg/hour ofbuprenorphine. Butrans® is indicated for the management of moderate tosevere chronic pain in patients requiring a continuous, around-the-clockopioid analgesic for an extended period of time. The prescribinginformation states that the most common adverse events (≧5%) reported bypatients in clinical trials include constipation. By virtue of thepresent invention, buprenorphine can be administered to patients at adose that will treat or prevent opioid-induced bowel dysfunction (e.g.,opioid-induced constipation) or other opioid induced adversepharmacodynamic responses.

In certain embodiments, the opioid-induced adverse pharmacodynamicresponse can be caused by the administration of an isolated or syntheticopioid that is typically endogenous to the patient (e.g., an endorphinor an enkephalin). In other embodiments, the opioid-induced adversepharmacodynamic response can be induced by administration to the patientof an opioid that is exogenous to the patient (e.g., oxycodone,morphine, codeine, oxymorphone, fentanyl, hydrocodone, hydromorphone,tramadol or a pharmaceutically acceptable salt thereof).

In certain embodiments, the opioid-induced adverse pharmacodynamicresponse can be induced by a peripherally restricted opioid, e.g., byadministration of a peripherally restricted opioid exogenous to thepatient by any suitable route (e.g., parenterally, subcutaneously orintramuscularly).

The peripherally restricted opioid analgesic utilized in the presentinvention (i) does not cross the blood brain or (ii) does notsignificantly cross the blood brain barrier (i.e., in an amountinsufficient to provide a pharmacological effect). The opioid analgesicutilized in the present invention can be peripherally restricted due to,e.g., (i) having an ionic charge (anionic or cationic), (ii) containinga quaternary amine, (iii) molecule size (e.g., proteins and peptides) or(iv) being a p-glycoprotein substrate.

In certain embodiments, the peripherally restricted opioid analgesic isloperamide or a pharmaceutically acceptable salt thereof or frakefamideor a pharmaceutically acceptable salt thereof.

When the peripherally restricted opioid analgesic is loperamide, theagent can be administered subcutaneously, e.g., in an amount from about0.1 mg/kg to about 10 mg/kg; from about 0.5 mg/kg to about 5 mg/kg, orin an amount of about 1 mg/kg, 2 mg/kg, 3 mg/kg, or 4 mg/kg.

In certain embodiments, the buprenorphine is administered concurrentlywith another opioid, and the buprenorphine serves to prevent, minimize,inhibit, ameliorate or reverse the opioid-induced adversepharmacodynamic response that might otherwise be associated with orcaused by the other opioid. Typically, the other opioid is administeredin an effective amount to provide an analgesic effect. In otherembodiments, the other opioid is administered in an effective amount totreat diarrhea, cough, anxiety (e.g., due to shortness of breath) oropioid dependence.

A patient receiving the buprenorphine therapy of the present inventionmay be opioid naive. Opioid naive patients may have initiated therapywith the other opioid prior to initiation of the buprenorphine therapy,or they may have initiated therapy with the other opioid concurrentlywith the initiation of the buprenorphine therapy. In other embodiments,the buprenorphine therapy can be initiated prior to the initiation oftherapy with the other opioid so as to provide a prophylactic effect.

Alternatively, a patient receiving the buprenorphine therapy of thepresent invention may previously have been dosed chronically withanother opioid so that he or she is now opioid tolerant.

The buprenorphine therapy of the present invention can be administeredafter the patient begins to exhibit symptoms of an opioid-inducedadverse pharmacodynamic response. Alternatively, the buprenorphinetherapy of the present invention can be administered prior to or at thesame time as a patient begins treatment with the other opioid in orderto reduce or avoid symptoms that might otherwise occur due toadministration of the other opioid alone.

In certain embodiments, the other opioid is administered before,concurrently with, or after the buprenorphine therapy of the presentinvention has an E_(max) of greater than about 25%, greater than about40%, greater than about 50%, greater than about 60%, greater than about70%, greater than about 80%, or greater than about 90%.

The buprenorphine administered in the present invention can be selectedfrom buprenorphine base, pharmaceutically acceptable salts, solvates,polymorphs, and mixtures thereof.

The buprenorphine used according to the present invention can beadministered by the same route as the other opioid. For example, thebuprenorphine and the other opioid can both be administered by the sameroute selected from the group consisting of oral, transdermal,sublingual, buccal, intranasal, rectal, subcutaneous, intramuscular,intravenous and parenteral.

In alternative embodiments, the buprenorphine used according to thepresent invention can be administered by a different route than theother opioid. For example, the buprenorphine and the other opioid can beindependently administered by different routes selected from the groupconsisting of oral, transdermal, sublingual, buccal, intranasal, rectal,subcutaneous, intramuscular, intravenous and parenteral.

Non-limiting examples of routes of administration for the presentinvention include transdermal buprenorphine with the other opioidadministered orally; transdermal buprenorphine with the other opioidadministered parenterally; transdermal buprenorphine with the otheropioid administered intranasally; transdermal buprenorphine with theother opioid administered sublingually; and transdermal buprenorphinewith the other opioid administered transdermally.

Other routes of administration of the present invention includesublingual buprenorphine with the other opioid administered orally;sublingual buprenorphine with the other opioid administeredparenterally; sublingual buprenorphine with the other opioidadministered intranasally; sublingual buprenorphine with the otheropioid administered sublingually; and sublingual buprenorphine with theother opioid administered transdermally.

Other routes of administration of the present invention include oralbuprenorphine with the other opioid administered orally; oralbuprenorphine with the other opioid administered parenterally; oralbuprenorphine with the other opioid administered intranasally; oralbuprenorphine with the other opioid administered sublingually; and oralbuprenorphine with the other opioid administered transdermally.

Other routes of administration of the present invention includeparenteral buprenorphine with the other opioid administered orally;parenteral buprenorphine with the other opioid administeredparenterally; parenteral buprenorphine with the other opioidadministered intranasally; parenteral buprenorphine with the otheropioid administered sublingually; and parenteral buprenorphine with theother opioid administered transdermally.

In one embodiment, the buprenorphine is administered in a transdermalsystem to provide, e.g., a dosing interval of about 24 hours, a dosinginterval of about 3 days, or a dosing interval of about 7 days.

The transdermal buprenorphine system can be formulated to administerbuprenorphine, e.g., at a rate from about 0.001 mcg/hour to about 50mcg/hour, from about 0.01 mcg/hour to about 40 mcg/hour, from about 0.05mcg/hour to about 30 mcg/hour, from about 0.1 mcg/hour to about 20mcg/hour or from about 0.5 mcg/hour to about 10 mcg/hour.

In other embodiments, the transdermal buprenorphine system can beformulated to administer buprenorphine, e.g., at a rate from about 0.001mcg/hour to about 5 mcg/hour, from about 0.01 mcg/hour to about 4mcg/hour, from about 0.05 mcg/hour to about 3 mcg/hour, from about 0.1mcg/hour to about 2 mcg/hour, or from about 0.5 mcg/hour to about 1mcg/hour.

In other embodiments, the transdermal buprenorphine system can beformulated to administer buprenorphine, e.g., at a rate of about 50mcg/hour, about 40 mcg/hour, about 30 mcg/hour, about 20 mcg/hour, about10 mcg/hour, about 5 mcg/hour, about 4 mcg/hour, about 3 mcg/hour, about2 mcg/hour, about 1 mcg/hour, about 0.5 mcg/hour, about 0.1 mcg/hour,about 0.05 mcg/hour, about 0.01 mcg/hour, or about 0.001 mcg/hour.

In one embodiment, the buprenorphine is administered sublingually. Thebuprenorphine can be formulated in a sublingual formulation to provide,e.g., a dosing interval of about 4 hours, a dosing interval of about 6hours, a dosing interval of about 8 hours, a dosing interval of about 12hours, or a dosing interval of about 24 hours.

The sublingual buprenorphine formulation can be formulated to administerbuprenorphine, e.g., at a dose of about 0.001 mg to about 10 mg, fromabout 0.01 mg to about 8 mg, from about 0.05 mg to about 6 mg, fromabout 0.1 mg to about 5 mg or from about 0.5 mg to about 4 mg, or fromabout 1 mg to about 2 mg.

In one embodiment, the buprenorphine is administered in an oral dosageform to provide, e.g., a dosing interval of about 4 hours, about 6hours, about 8 hours, about 12 hours or about 24 hours.

The oral buprenorphine dosage form can be formulated to administerbuprenorphine, e.g., at a dose of less than about 500 mg, less thanabout 400 mg, less than about 350 mg, less than about 300 mg, less thanabout 250 mg, less than about 200 mg, less than about 150 mg, less thanabout 100 mg, less than about 90 mg, less than about 80 mg, less thanabout 70 mg, less than about 60 mg, less than about 50 mg, less thanabout 40 mg, less than about 30 mg, less than about 20 mg, less thanabout 10 mg, less than about 9 mg, less than about 8 mg, less than about7 mg, less than about 6 mg, less than about 5 mg, less than about 4 mg,less than about 3 mg, less than about 2 mg, less than about 1 mg, lessthan about 0.9 mg, less than about 0.8 mg, less than about 0.7 mg, lessthan about 0.6 mg, less than about 0.5 mg, less than about 0.4 mg, lessthan about 0.3 mg, less than about 0.2 mg or less than about 0.1 mg.

In other embodiments, the oral buprenorphine dosage form can beformulated to administer buprenorphine, e.g., at a dose of from about 1mg to about 500 mg, from about 1 mg to about 400 mg, from about 1 mg toabout 350 mg, from about 1 mg to about 300 mg, from about 1 mg to about250 mg, from about 1 mg to about 200 mg, from about 1 mg to about 150mg, from about 1 mg to about 100 mg, from about 1 mg to about 90 mg,from about 1 mg to about 80 mg, from about 1 mg to about 70 mg, fromabout 1 mg to about 60 mg, from about 1 mg to about 50 mg, from about 1mg to about 40 mg, or from about 1 mg to about 30 mg.

In other embodiments, the oral buprenorphine dosage form can beformulated to administer buprenorphine, e.g., at a dose of from about 30mg to about 500 mg, from about 30 mg to about 400 mg, from about 30 mgto about 350 mg, from about 30 mg to about 300 mg, from about 30 mg toabout 250 mg, from about 30 mg to about 200 mg, from about 30 mg toabout 150 mg, from about 30 mg to about 100 mg, from about 30 mg toabout 90 mg, from about 30 mg to about 80 mg, from about 30 mg to about70 mg, from about 30 mg to about 60 mg, from about 30 mg to about 50 mg,or from about 30 mg to about 40 mg.

In other embodiments, the oral buprenorphine dosage form can beformulated to administer buprenorphine, e.g., at a dose of from about0.1 mg to about 30 mg, from about 0.2 mg to about 30 mg, from about 0.3mg to about 30 mg, from about 0.4 mg to about 30 mg, from about 0.5 mgto about 30 mg, from about 0.6 mg to about 30 mg, from about 0.7 mg toabout 30 mg, from about 0.8 mg to about 30 mg, from about 0.9 mg toabout 30 mg, from about 2 mg to about 30 mg, from about 3 mg to about 30mg, from about 4 mg to about 30 mg, from about 5 mg to about 30 mg, fromabout 6 mg to about 30 mg, from about 7 mg to about 30 mg, from about 8mg to about 30 mg, from about 9 mg to about 30 mg or from about 10 mg toabout 30 mg.

In other embodiments, the oral buprenorphine dosage form can beformulated to administer buprenorphine, e.g., at a dose of from about 3mg to about 500 mg, from about 3 mg to about 400 mg, from about 3 mg toabout 350 mg, from about 3 mg to about 300 mg, from about 3 mg to about250 mg, from about 3 mg to about 200 mg, from about 3 mg to about 150mg, from about 3 mg to about 100 mg, from about 3 mg to about 90 mg,from about 3 mg to about 80 mg, from about 3 mg to about 70 mg, fromabout 3 mg to about 60 mg, from about 3 mg to about 50 mg, from about 3mg to about 40 mg, from about 3 mg to about 30 mg, from about 3 mg toabout 20 mg or from about 3 mg to about 10 mg.

In other embodiments, the oral buprenorphine dosage form can beformulated to administer buprenorphine, e.g., at a dose of from about0.1 mg to about 3 mg, from about 0.2 mg to about 3 mg, from about 0.3 mgto about 3 mg, from about 0.4 mg to about 3 mg, from about 0.5 mg toabout 3 mg, from about 0.6 mg to about 3 mg, from about 0.7 mg to about3 mg, from about 0.8 mg to about 3 mg, from about 0.9 mg to about 3 mg,from about 1 mg to about 3 mg, or from about 2 mg to about 3 mg.

In certain embodiments, the buprenorphine is administered orally in anamount of from about 0.1 mg to about 500 mg, from about 0.1 mg to about400 mg, from about 0.1 mg to about 300 mg, from about 0.1 mg to about200 mg, from about 0.1 mg to about 100 mg, from about 0.1 mg to about 90mg, from about 0.1 mg to about 80 mg, from about 0.1 mg to about 70 mg,from about 0.1 mg to about 60 mg, from about 0.1 mg to about 50 mg, fromabout 0.1 mg to about 40 mg, from about 0.1 mg to about 30 mg, fromabout 0.1 mg to about 20 mg, from about 0.1 mg to about 10 mg, or fromabout 0.1 mg to about 5 mg.

The buprenorphine of the present invention can be administered by anyroute (e.g., oral or transdermal or subcutaneous) to provide at steadystate, e.g., from about 0.001 mg/kg to about 1 mg/kg, from about 0.005mg/kg to about 0.5 mg/kg or from about 0.05 mg/kg to about 0.1 mg/kg. Inother embodiments, the buprenorphine of the present invention can beadministered by any route (e.g., oral) to provide at steady state, e.g.,about 1 mg/kg, about 0.5 mg/kg, about 0.1 mg/kg, about 0.05 mg/kg, about0.005 mg/kg or about 0.001 mg/kg. The buprenorphine can be administeredfor any suitable time, e.g., for the full duration of therapy with theother opioid or for a fraction of the full duration of therapy with theother opioid.

The buprenorphine of the present invention can be administered by anyroute (e.g., oral or transdermal or subcutaneous) to provide after firstadministration or at steady state, a C_(max), e.g., from about 0.001ng/ml to about 15 ng/ml, from about 0.005 ng/ml to about 12 ng/ml, fromabout 0.05 ng/ml to about 10 ng/ml, from about 0.05 ng/ml to about 1ng/ml, from about 0.05 ng/ml to about 0.5 ng/ml from about 0.5 ng/ml toabout 8 ng/ml, from about 1.0 ng/ml to about 5 ng/ml, or from about 2ng/ml to about 4 ng/ml.

In other embodiments, the buprenorphine of the present invention can beadministered by any route (e.g. oral or transdermal or subcutaneous) toprovide after first administration or at steady state, a C_(max), e.g.,of about 0.001 ng/ml, about 0.01 ng/ml, about 0.1 ng/ml, about 1 ng/ml,about 2 ng/ml, about 3 ng/ml, about 4 ng/ml, or about 5 ng/ml.

In other embodiments, the buprenorphine of the present invention can beadministered by any route (e.g. oral or transdermal or subcutaneous) toprovide after first administration or at steady state, a C_(max), e.g.,of less than about 5 ng/ml, less than about 4 ng/ml, less than about 3ng/ml, less than about 2 ng/ml, less than about 1 ng/ml, less than about0.1 ng/ml, less than about 0.01 ng/ml, less than about 0.001 ng/ml orless than about 0.0001 ng/ml.

In other embodiments, the buprenorphine of the present invention can beadministered by any route (e.g. oral or transdermal or subcutaneous) toprovide after first administration or at steady state, an AUC, e.g.,from about 0.01 ng/ml*hr to about 100 ng/ml*hr, from about 0.1 ng/ml*hrto about 75 ng/ml*hr, from about 1.0 ng/ml*hr to about 50 ng/ml*hr, fromabout 5.0 ng/ml*hr to about 40 ng/ml*hr, or from about 10 ng/ml*hr toabout 30 ng/ml*hr.

In certain embodiments, the buprenorphine is administered orally andprovides treatment or prevention of an opioid-induced adversepharmacodynamic response (e.g., constipation) without a circulatingplasma level, or a plasma level below detectable limits.

The steady state or first administration AUC and C_(max) valuesdisclosed herein may be obtained by any suitable route of administrationsuch as transdermally, sublingually, buccally, orally, subcutaneously,intramuscularly or by a parenteral depot injection. A depot injection ofbuprenorphine may be administered by implantation (for example,subcutaneously or intramuscularly) or by intramuscular injection. Insuch formulations, the release of the buprenorphine is controlled byformulation with a suitable polymeric or hydrophobic material (e.g.,polylactic glycolic acid), an ion exchange resin, or as a sparinglysoluble derivative (e.g., a sparingly soluble salt). Preferably, thedepot injection provides a dosing interval from about 1 day to about 3months, or about 3 days, about 7 days, about 10 days, about 14 days,about 21 days, about one month, about 6 weeks, or about 2 months.

The other opioid can be selected from the group consisting ofalfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine,bezitramide, butorphanol, clonitazene, codeine, desomorphine,dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine,dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene,dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine,ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin,hydrocodone, hydromorphone, hydroxypethidine, isomethadone,ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine,meptazinol, metazocine, methadone, metopon, morphine, myrophine,nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone,nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone,papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine,phenoperidine, piminodine, piritramide, proheptazine, promedol,properidine, propiram, propoxyphene, sufentanil, tilidine, tramadol,pharmaceutically acceptable salts thereof, and mixtures thereof.

In certain embodiments, the other opioid agonist is selected from thegroup consisting of codeine, fentanyl, hydromorphone, hydrocodone,oxycodone, dihydrocodeine, dihydromorphine, morphine, tramadol,oxymorphone, pharmaceutically acceptable salts thereof, and mixturesthereof.

In certain embodiments, the other opioid is oxycodone or apharmaceutically acceptable salt thereof.

In certain embodiments, the other opioid is hydrocodone or apharmaceutically acceptable salt thereof.

In certain embodiments, the other opioid is hydromorphone or apharmaceutically acceptable salt thereof.

In certain embodiments, the other opioid is oxymorphone or apharmaceutically acceptable salt thereof.

In certain embodiments, the other opioid is morphine or apharmaceutically acceptable salt thereof.

The other opioid may be formulated in the free base form, or as apharmaceutically acceptable salt thereof.

The other opioid can be administered as a transdermal patch, a liquidoral dosage form, or as a solid oral dosage form in either immediate orcontrolled release form.

The other opioid can be administered in controlled release form with adosing interval, e.g., of about 8 hours, about 12 hours or about 24hours. The other opioid can alternatively be administered in immediaterelease form with a dosing interval, e.g., of about 2 hours, about 4hours, about 6 hours or about 8 hours. The other opioid, either incontrolled release form or immediate release form, can be utilized inthe present invention either alone or in combination with a non-opioidanalgesic such as an NSAID (e.g., acetaminophen, aspirin, ibuprofen,naproxen, diclofenac, or a COX-2 inhibitor). Certain combinationproducts can contain in addition to the other opioid, from about 200 mgto about 800 mg acetaminophen (e.g., about 325 mg, about 500 mg or about650 mg); from about 200 mg to about 800 mg aspirin (e.g., about 325 mgor about 500 mg); or about 200 mg to about 1000 mg ibuprofen (e.g.,about 200 mg, about 400 mg, about 600 mg or about 800 mg).

The other opioid in controlled release form can be oxycodonehydrochloride in an amount, e.g., from about 10 mg to about 160 mg perunit dose. In specific embodiments, each unit dose can provide an amountof oxycodone hydrochloride of about 10 mg, about 20 mg, about 30 mg,about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about100 mg, about 120 mg or about 160 mg. Controlled release oxycodonehydrochloride utilized in the present invention may be Oxycontin®(Oxycodone hydrochloride extended release tablets) commerciallyavailable from Purdue Pharma. The oxycodone hydrochloride in immediaterelease form can be in an amount from about 2.5 mg to about 50 mg, about2.5 mg, about 4.5 mg; about 4.8355 mg; about 5 mg, about 7.5 mg, about10 mg, about 15 mg, about 20 mg, or about 30 mg. Immediate releaseoxycodone hydrochloride utilized in the present invention may be Tylox®(acetaminophen, oxycodone hydrochloride); Roxilox® (acetaminophen,oxycodone hydrochloride); Percocet® (acetaminophen, oxycodonehydrochloride); Oxycet® (acetaminophen, oxycodone hydrochloride); Roxicet(acetaminophen, oxycodone hydrochloride); Percodan® (aspirin, oxycodonehydrochloride); Oxecta® (acetaminophen, oxycodone hydrochloride); orRoxicodone® (oxycodone hydrochloride).

The other opioid in controlled release form can be tramadolhydrochloride in an amount, e.g., from about 100 mg to about 300 mg perunit dose. In specific embodiments, each unit dose can provide an amountof tramadol hydrochloride of about 100 mg, about 150 mg, about 200 mg,about 250 mg, or about 300 mg. Tramadol hydrochloride utilized in thepresent invention may be Conzip® (Tramadol hydrochloride extendedrelease capsules); Ryzolt® (Tramadol hydrochloride extended releasetablets); or Ultram ER® (Tramadol hydrochloride extended releasecapsules). Immediate release tramadol hydrochloride utilized in thepresent invention may be Ultracet® (acetaminophen, tramadolhydrochloride); or Rybix ODT® (tramadol hydrochloride orallydisintegrating tablet).

The other opioid in controlled release form can be oxymorphonehydrochloride in an amount, e.g., from about 5 mg to about 40 mg perunit dose. In specific embodiments, each unit dose can provide an amountof oxymorphone hydrochloride of about 5 mg, about 10 mg, about 15 mg,about 20 mg, about 25 mg, about 30 mg, about 35 mg or about 40 mg.Oxymorphone hydrochloride utilized in the present invention may be OpanaER® (Oxymorphone hydrochloride extended release tablets). Immediaterelease oxymorphone hydrochloride utilized in the present invention maybe Opana® (oxymorphone hydrochloride).

The other opioid in controlled release form can be hydrocodonebitartrate in an amount, e.g., from about 2 mg to about 200 mg per unitdose. In specific embodiments, each unit dose can provide an amount ofhydrocodone bitartrate of about 20 mg, about 30 mg, about 40 mg, about60 mg, about 80 mg, about 100 mg or about 120 mg. Immediate releasehydrocodone bitartrate utilized in the present invention may be Vicodin®(acetaminophen, hydrocodone bitartrate); Zydone® (acetaminophen,hydrocodone bitartrate); Anexsia® (acetaminophen, hydrocodonebitartrate); Lortab® (acetaminophen, hydrocodone bitartrate) orVicoprofen® (ibuprofen, hydrocodone bitartrate).

The other opioid in controlled release form can be morphine sulfate inan amount, e.g., from about 2 mg to about 200 mg per unit dose. Inspecific embodiments, each unit dose can provide an amount of morphinesulfate of about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 60mg, about 80 mg, about 100 mg, about 120 mg or about 200 mg. Morphinesulfate utilized in the present invention may be Avinza® (Morphinesulfate extended release capsules); Kadian® (Morphine sulfate extendedrelease capsules); or MS Contin® (Morphine sulfate extended releasetablets).

The other opioid in controlled release form can be hydromorphonehydrochloride in an amount, e.g., from about 2 mg to about 200 mg perunit dose. In specific embodiments, each unit dose can provide an amountof hydromorphone hydrochloride of about 8 mg, about 12 mg, about 16 mg,about 32 mg, about 64 mg, or about 128 mg; or about 20 mg, about 30 mg,about 40 mg, about 60 mg, about 80 mg, about 100 mg or about 120 mg.Hydromorphone hydrochloride utilized in the present invention may beExalgo® (Hydromorphone hydrochloride extended-release tablets);Palladone® (Hydromorphone hydrochloride extended-release capsules); orDilaudid® (Hydromorphone hydrochloride oral tablets).

The other opioid in controlled release form can be tapentadolhydrochloride in an amount, e.g., from about 2 mg to about 400 mg perunit dose. In specific embodiments, each unit dose can provide an amountof tapentadol hydrochloride of about 50 mg, about 100 mg, about 150 mg,or about 250 mg. Tapentadol utilized in the present invention may beNucynta ER® (Tapentadol extended release oral tablets) or Nucynta®(Tapentadol oral tablets).

The other opioid can be fentanyl disposed in a transdermal system thatdelivers the fentanyl in an amount, e.g., of about 12.5 mcg/hr; about 25mcg/hr; about 50 mcg/hr; about 75 mcg/hr or about 100 mcg/hr. Fentanylutilized in the present invention can be Duragesic® (fentanyl film,extended release).

In certain embodiments, the ratio of the daily dose of buprenorphine tothe other opioid is, e.g., less than about 1:5 (w/w), less than about1:10 (w/w), less than about 1:50 (w/w), less than about 1:5 (w/w), lessthan about 1:10 (w/w), less than about 1:25 (w/w), less than about 1:50(w/w), less than about 1:75 (w/w), less than about 1:100 (w/w), lessthan about 1:150 (w/w), less than about 1:200 (w/w), less than about1:250 (w/w), less than about 1:500 (w/w), less than about 1:600 (w/w),less than about 1:700 (w/w), less than about 1:850 (w/w), or less thanabout 1:1000 (w/w).

In certain embodiments, the buprenorphine is administered transdermallyin an amount of about 5 mcg/hr or less concurrently with oral controlledrelease oxycodone hydrochloride in a unit dose of about 10 mg, about 20mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg,about 80 mg, about 100 mg, about 120 mg or about 160 mg. Preferably, thebuprenorphine dosing interval is about 3 days or about 7 days and theoxycodone dosing interval is about 12 hours.

In certain embodiments, the buprenorphine is administered transdermallyin an amount of about 5 mcg/hr or less concurrently with oral controlledrelease oxymorphone hydrochloride in a unit dose of about 5 mg, about 10mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg orabout 40 mg. Preferably, the buprenorphine dosing interval is about 3days or about 7 days, and the oxymorphone dosing interval is about 12hours.

In certain embodiments, the buprenorphine is administered transdermallyin an amount of about 5 mcg/hr or less concurrently with oral controlledrelease hydrocodone bitartrate in a unit dose of about 20 mg, about 30mg, about 40 mg, about 60 mg, about 80 mg, about 100 mg or about 120 mg.Preferably, the buprenorphine dosing interval is about 3 days or about 7days, and the hydrocodone dosing interval is about 12 hours or about 24hours.

In certain embodiments, the buprenorphine is administered transdermallyin an amount of about 5 mcg/hr or less concurrently with oral controlledrelease morphine sulfate in a unit dose of about 15 mg, about 30 mg,about 40 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg orabout 200 mg. Preferably, the buprenorphine dosing interval is about 3days or about 7 days, and the morphine dosing interval is about 12 hoursor about 24 hours.

In certain embodiments, the buprenorphine is administered transdermallyin an amount of about 5 mcg/hr or less concurrently with oral controlledrelease hydromorphone hydrochloride in a unit dose of about 8 mg, about12 mg, about 16 mg, about 32 mg, about 64 mg, or about 128 mg.Preferably, the buprenorphine dosing interval is about 3 days or about 7days, and the hydromorphone dosing interval is about 12 hours.

In certain embodiments, the buprenorphine is administered transdermallyin an amount of about 5 mcg/hr or less concurrently with transdermallyadministered fentanyl in an amount of about 12.5 mcg/hr; about 25mcg/hr; about 50 mcg/hr; about 75 mcg/hr or about 100 mcg/hr.Preferably, the buprenorphine dosing interval is about 3 or 7 days andthe fentanyl dosing interval is about 3 or 7 days.

In certain embodiments, the buprenorphine is administered orallyconcurrently with oral administration of the other opioid. Thebuprenorphine can be in the same oral dosage form as the other opioid orcan be in a separate oral dosage form as the other opioid.

In certain embodiments, the buprenorphine is administered orally in anamount of about 5 mg or less, about 4 mg or less, about 2 mg or less,about 1 mg or less, about 0.5 mg or less, about 0.25 mg or less or about0.1 mg or less concurrently with oral controlled release oxycodonehydrochloride in a unit dose of about 10 mg, about 20 mg, about 30 mg,about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about100 mg, about 120 mg or about 160 mg. Preferably, the buprenorphinedosing interval is about 12 hours or about 24 hours and the oxycodonedosing interval is about 12 hours.

In certain embodiments, the buprenorphine is administered orally in anamount of about 5 mg or less, about 4 mg or less, about 2 mg or less,about 1 mg or less, about 0.5 mg or less, about 0.25 mg or less or about0.1 mg or less concurrently with oral controlled release oxymorphonehydrochloride in a unit dose of about 5 mg, about 10 mg, about 15 mg,about 20 mg, about 25 mg, about 30 mg, about 35 mg or about 40 mg.Preferably, the buprenorphine dosing interval is about 12 hours or about24 hours, and the oxymorphone dosing interval is about 12 hours.

In certain embodiments, the buprenorphine is administered orally in anamount of about 5 mg or less, about 4 mg or less, about 2 mg or less,about 1 mg or less, about 0.5 mg or less, about 0.25 mg or less or about0.1 mg or less concurrently with oral controlled release hydrocodonebitartrate in a unit dose of about 20 mg, about 30 mg, about 40 mg,about 60 mg, about 80 mg, about 100 mg or about 120 mg. Preferably, thebuprenorphine dosing interval is about 12 hours or about 24 hours, andthe hydrocodone dosing interval is about 12 hours or about 24 hours.

In certain embodiments, the buprenorphine is administered orally in anamount of about 5 mg or less, about 4 mg or less, about 2 mg or less,about 1 mg or less, about 0.5 mg or less, about 0.25 mg or less or about0.1 mg or less concurrently with oral controlled release morphinesulfate in a unit dose of about 15 mg, about 30 mg, about 40 mg, about60 mg, about 80 mg, about 100 mg, about 120 mg or about 200 mg.Preferably, the buprenorphine dosing interval is about 12 hours or about24 hours, and the morphine dosing interval is about 12 hours or about 24hours.

In certain embodiments, the buprenorphine is administered orally in anamount of about 5 mg or less, about 4 mg or less, about 2 mg or less,about 1 mg or less, about 0.5 mg or less, about 0.25 mg or less or about0.1 mg or less concurrently with oral controlled release hydromorphonehydrochloride in a unit dose of about 8 mg, about 12 mg, about 16 mg,about 32 mg, about 64 mg, or about 128 mg. Preferably, the buprenorphinedosing interval is about 12 hours or about 24 hours, and thehydromorphone dosing interval is about 12 hours.

In certain embodiments, the buprenorphine is administered orally in anamount of about 5 mg or less, about 4 mg or less, about 2 mg or less,about 1 mg or less, about 0.5 mg or less, about 0.25 mg or less or about0.1 mg or less concurrently with transdermally administered fentanyl inan amount of about 12.5 mcg/hr; about 25 mcg/hr; about 50 mcg/hr; about75 mcg/hr or about 100 mcg/hr. Preferably, the buprenorphine dosinginterval is about 12 hours or about 24 hours and the fentanyl dosinginterval is about 3 or 7 days.

The buprenorphine and the other opioid can both be formulated to provide(i) an immediate release from the same or different oral dosage forms or(ii) controlled release from the same or different dosage forms.

In alternate embodiments, the buprenorphine can be formulated forimmediate release and the other opioid can be formulated for controlledrelease, from the same or different oral dosage forms.

In further embodiments, the buprenorphine can be formulated forcontrolled release and the other opioid can be formulated for immediaterelease, from the same or different oral dosage forms.

Preferably, the oral dosage form containing either the buprenorphine,the other opioid, or both agents, is in the form of a tablet or capsule.

In formulations containing both agents, the buprenorphine and the otheropioid can be commingled in a tablet or capsule.

In a tablet formulation, the core can contain the buprenorphine which islayered with a coating of the other opioid. Alternatively, the core cancontain the other opioid which is layered with a coating of thebuprenorphine. In other embodiments, the formulation can be in a laminararrangement such that the buprenorphine and the other opioid are layeredin at least a bilayer tablet.

In capsule formulations, the agents can be in the same multiparticulateformulation or in separate multiparticulate formulations that arecontained in a pharmaceutically acceptable capsule (e.g., a gelatincapsule). The components of the multiparticulate formulation can be inthe form of a core containing the buprenorphine which is layered with acoating of the other opioid. Alternatively, the components of themultiparticulate formulation can be in the form of a core containing theother opioid which is layered with a coating of the buprenorphine. Inother embodiments, the capsule can contain a granulation or powder blendcontaining both the buprenorphine and the other opioid, or separategranulations or powders each containing the buprenorphine or the otheropioid.

In oral formulations, the buprenorphine and/or the other opioid can beformulated to provide a delayed release in order to target release at aspecific site in the gastro-intestinal tract (e.g., the intestine or thecolon). The delayed release can be obtained with an enteric coating onthe tablet, multiparticulates, capsule or any other dosage form orcomponent of a dosage form, as appropriate. Enteric materials that canbe utilized to provide a delayed release of buprenorphine and/or theother opioid include, e.g., shellac, cellulose acetate phthalate (CAP),polyvinyl acetate phthalate (PVAP), hydroxypropylmethylcellulosephthalate, methacrylic acid ester copolymers and zein.

The invention further encompasses kits that can simplify theadministration of buprenorphine concurrently with another opioid inorder to prevent or treat an opioid-induced adverse pharmacodynamicresponse. A typical kit of the invention comprises a unit dosage form ofbuprenorphine and a unit dosage form of another opioid.

In one embodiment, the kit comprises one container holding at least oneunit dose of buprenorphine and another container holding at least oneunit dose of another opioid. The kit can further comprise a label orprinted instructions instructing the use of the buprenorphine to preventor treat an opioid-induced adverse pharmacodynamic response.

Kits of the invention can further comprise a device that is useful foradministering the unit dosage forms. Examples of such a device include,but are not limited to, a syringe, a drip bag, a patch, an inhaler, andan enema bag.

In one embodiment, buprenorphine is included in the kit as a transdermalpatch, e.g., suitable for administration every 3 or 7 days, along withan amount of unit doses of a controlled or immediate release opioid(e.g., oxycodone hydrochloride or oxymorphone hydrochloride) for anequivalent time period. For example, a kit of the invention can includea 7 day transdermal buprenorphine patch and 14 controlled releaseoxycodone hydrochloride tablets (to be administered every 12 hours). Akit of the invention can include any combination of a buprenorphineformulation with a formulation the other opioid as disclosed herein.When oral solid dosage forms are included in a kit, the formulations canbe contained in a blister package.

The buprenorphine can be in an amount that (i) does not cause a decreasein the analgesic effectiveness of the other opioid, or (ii) does notcause a substantial decrease in the analgesic effectiveness of the otheropioid, or (iii) provides an increase in analgesia as compared to theadministration of the other opioid alone.

The concentration of buprenorphine that affects the analgesic efficacyof the concurrently administered other opioid as compared to theconcentration of buprenorphine that prevents or treats opioid inducedadverse pharmacodynamic response (e.g., bowel dysfunction) depends onthe identity of the other opioid that is concurrently beingadministered. Preferably, the window of separation is sufficient suchthat the buprenorphine effectively prevents or treats the opioid inducedadverse pharmacodynamic response without affecting the analgesic potencyof the opioid. Oxycodone is a specific opioid with a sufficient windowthat enables the prevention or treatment of the opioid-induced adversepharmacodynamic response with buprenorphine with a reduced likelihood ofthe oxycodone having its analgesic effect compromised.

In preferred embodiments, the minimal concentration of buprenorphinethat affects the analgesic efficacy of the concurrently administeredother opioid is about 100 times the concentration of buprenorphine thatprevents or treats opioid induced adverse pharmacodynamic response. Inother embodiments, the minimal concentration of buprenorphine thataffects the analgesic effectiveness of the concurrently administeredother opioid is about 90 times, about 80 times, about 70 times, about 60times, about 50 times, about 40 times, about 30 times, about 20 times 10times, about 5 times, or about 2 times the minimal concentration ofbuprenorphine that prevents or treats the opioid induced adversepharmacodynamic response.

Formulations of Buprenorphine and the Other Opioid

The buprenorphine and/or the other opioid can be administered as acomponent of a pharmaceutical composition that comprises apharmaceutically acceptable carrier or excipient. The buprenorphineand/or the other opioid can be formulated as (i) separate formulationsintended for different routes of administration, (ii) separateformulations intended for the same route of administration, or (iii) inthe same formulation to be administered together by the same route ofadministration. The pharmaceutical compositions can be administered byany appropriate route, as determined by the medical practitioner.Methods of administration may include intradermal, intramuscular,intraperitoneal, parenteral, intravenous, subcutaneous, intranasal,epidural, oral, sublingual, buccal, intracerebral, intravaginal,transdermal, transmucosal, rectal, by inhalation, or topical(particularly the skin).

Pharmaceutical compositions of the invention can take the form ofsolutions, suspensions, emulsions, tablets, pills, pellets,multi-particulates, capsules, capsules containing liquids, capsulescontaining powders, capsules containing multi-particulates, lozenges,sustained-release formulations, suppositories, aerosols, sprays, or anyother form suitable for use. In one embodiment, the composition is inthe form of a capsule (see, e.g., U.S. Pat. No. 5,698,155). Otherexamples of suitable pharmaceutical excipients are described inRemington's Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro ed.,19th ed. 1995), incorporated herein by reference.

Pharmaceutical compositions of the invention preferably comprise asuitable amount of a pharmaceutically acceptable excipient so as toprovide the form for proper administration to the patient. Such apharmaceutical excipient can be a diluent, suspending agent,solubilizer, binder, disintegrant, buffer, glidant, preservative,coloring agent, lubricant, and the like. The pharmaceutical excipientcan be a liquid, such as water or an oil, including those of petroleum,animal, vegetable, or synthetic origin, such as peanut oil, soybean oil,mineral oil, sesame oil, and the like. The pharmaceutical excipient canbe saline, gum acacia, gelatin, starch paste, talc, keratin, colloidalsilica, urea, and the like. In addition, auxiliary, stabilizing,thickening, lubricating, and coloring agents can be used. In oneembodiment, the pharmaceutically acceptable excipient is sterile whenadministered to a patient. Water is a particularly useful excipient whenthe pharmaceutical composition is administered intravenously. Salinesolutions and aqueous dextrose and glycerol solutions can also beemployed as liquid excipients, particularly for injectable solutions.Suitable pharmaceutical excipients also include starch, glucose,lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodiumstearate, glycerol monostearate, talc, sodium chloride, dried skim milk,glycerol, propylene glycol, water, ethanol, and the like. The inventioncompositions, if desired, can also contain minor amounts of wetting oremulsifying agents, or pH buffering agents. Specific examples ofpharmaceutically acceptable carriers and excipients that can be used toformulate oral dosage forms are described in the Handbook ofPharmaceutical Excipients, American Pharmaceutical Association (1986).

In certain embodiments, the pharmaceutical compositions are formulatedfor oral administration. A pharmaceutical composition of the inventionto be orally delivered can be in the form of tablets, capsules, gelcaps,caplets, lozenges, aqueous or oily solutions, suspensions, granules,powders, emulsions, syrups, or elixirs, for example. When thebuprenorphine and/or the other opioid is incorporated into oral tablets,such tablets can be compressed, tablet triturates, enteric-coated,sugar-coated, film-coated, multiply compressed or multiply layered.

An orally administered pharmaceutical composition can contain one ormore additional agents such as, for example, sweetening agents such asfructose, aspartame or saccharin; flavoring agents such as peppermint,oil of wintergreen, or cherry; coloring agents; and preserving agents,and stabilizers, to provide stable, pharmaceutically palatable dosageforms. Techniques and compositions for making solid oral dosage formsare described in Pharmaceutical Dosage Forms: Tablets (Lieberman,Lachman and Schwartz, eds., 2nd ed.) published by Marcel Dekker, Inc.Techniques and compositions for making tablets (compressed and molded),capsules (hard and soft gelatin) and pills are also described inRemington's Pharmaceutical Sciences 1553-1593 (Arthur Osol, ed.,16.sup.th ed., Mack Publishing, Easton, Pa. 1980). Liquid oral dosageforms include aqueous and nonaqueous solutions, emulsions, suspensions,and solutions and/or suspensions reconstituted from non-effervescentgranules, optionally containing one or more suitable solvents,preservatives, emulsifying agents, suspending agents, diluents,sweeteners, coloring agents, flavoring agents, and the like. Techniquesand compositions for making liquid oral dosage forms are described inPharmaceutical Dosage Forms: Disperse Systems, (Lieberman, Rieger andBanker, eds.) published by Marcel Dekker, Inc.

When the buprenorphine and/or the other opioid is formulated forparenteral administration by injection (e.g., continuous infusion orbolus injection), the formulation can be in the form of a suspension,solution, or emulsion in an oily or aqueous vehicle, and suchformulations can further comprise pharmaceutically necessary additivessuch as one or more stabilizing agents, suspending agents, dispersingagents, and the like. When the buprenorphine and/or the other opioid isto be injected parenterally, it can be, e.g., in the form of an isotonicsterile solution. The buprenorphine and/or the other opioid can also bein the form of a powder for reconstitution as an injectable formulation.

In certain embodiments, the buprenorphine and/or the other opioid isformulated into a pharmaceutical composition for intravenousadministration. Typically, such compositions comprise sterile isotonicaqueous buffer. Where necessary, the compositions can also include asolubilizing agent. A pharmaceutical composition for intravenousadministration can optionally include a local anesthetic such asbenzocaine or prilocaine to lessen pain at the site of the injection.Generally, the ingredients are supplied either separately or mixedtogether in unit dosage form, for example, as a dry lyophilized powderor water-free concentrate in a hermetically sealed container such as anampule or sachette indicating the quantity of active agent. Where thebuprenorphine and/or the other opioid is to be administered by infusion,it can be dispensed, for example, with an infusion bottle containingsterile pharmaceutical grade water or saline. When the buprenorphineand/or the other opioid is administered by injection, an ampule ofsterile water for injection or saline can be provided so that theingredients can be mixed prior to administration.

When the buprenorphine and/or the other opioid is to be administered byinhalation, it can be formulated into a dry aerosol, or an aqueous orpartially aqueous solution.

In another embodiment, the buprenorphine and/or the other opioid can bedelivered in a vesicle, in particular a liposome (see Langer, Science249:1527-1533 (1990); and Treat et al., Liposomes in the Therapy ofInfectious Disease and Cancer 317-327 and 353-365 (1989)).

In certain embodiments, the buprenorphine and/or the other opioid can bedelivered in an immediate release form. In other embodiments, thebuprenorphine and/or the other opioid can be delivered in acontrolled-release system or sustained-release system. Controlled- orsustained-release pharmaceutical compositions can have a common goal ofimproving drug therapy over the results achieved by their non-controlledor non-sustained-release counterparts. Advantages of controlled- orsustained-release compositions include extended activity of the drug,reduced dosage frequency, and increased compliance. In addition,controlled- or sustained-release compositions can favorably affect thetime of onset of action or other characteristics, such as blood levelsof the buprenorphine and/or the other opioid, and can thus reduce theoccurrence of adverse side effects.

Controlled- or sustained-release compositions can initially release anamount of the buprenorphine and/or the other opioid that promptlyproduces the desired therapeutic or prophylactic effect, and graduallyand continually release other amounts of the buprenorphine and/or theother opioid to maintain a level of therapeutic or prophylactic effectover an extended period of time. To maintain a constant level of thebuprenorphine and/or the other opioid in the body, the pharmaceuticalcomposition can release the active(s) from the dosage form at a ratethat will replace the amount of active(s) being metabolized and excretedfrom the body. Controlled or sustained release of an active ingredientcan be triggered by any of various conditions, including but not limitedto, changes in pH, changes in temperature, concentration or availabilityof enzymes, concentration or availability of water, or otherphysiological conditions or compounds.

Controlled-release and sustained-release means for use according to thepresent invention may be selected from those known in the art. Examplesinclude, but are not limited to, those described in U.S. Pat. Nos.3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533;5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; and5,733,566, each of which is incorporated herein by reference. Suchdosage forms can be used to provide controlled- or sustained-release ofone or both of the active ingredients using, for example,hydropropylmethyl cellulose, other polymer matrices, gels, permeablemembranes, osmotic systems, multilayer coatings, microparticles,multiparticulates, liposomes, microspheres, or a combination thereof toprovide the desired release profile in varying proportions. Suitablecontrolled- or sustained-release formulations known in the art,including those described herein, can be readily selected for use withthe active ingredients of the invention in view of this disclosure. Seealso Goodson, “Dental Applications” (pp. 115-138) in MedicalApplications of Controlled Release, Vol. 2, Applications and Evaluation,R. S. Langer and D. L. Wise eds., CRC Press (1984). Other controlled- orsustained-release systems that are discussed in the review by Langer,Science 249:1527-1533 (1990) can be selected for use according to thepresent invention. In one embodiment, a pump can be used (Langer,Science 249:1527-1533 (1990); Sefton, CRC Crit. Ref Biomed. Eng. 14:201(1987); Buchwald et al., Surgery 88:507 (1980); and Saudek et al., N.Engl. J. Med. 321:574 (1989)). In another embodiment, polymericmaterials can be used (see Medical Applications of Controlled Release(Langer and Wise eds., 1974); Controlled Drug Bioavailability, DrugProduct Design and Performance (Smolen and Ball eds., 1984); Ranger andPeppas, J. Macromol. Sci. Rev. Macromol. Chem. 23:61 (1983); Levy etal., Science 228:190 (1985); During et al., Ann. Neurol. 25:351 (1989);and Howard et al., J. Neurosurg. 71:105 (1989)).

When in tablet or pill form, a pharmaceutical composition of theinvention can be coated to delay disintegration and absorption in thegastrointestinal tract thereby providing targeted release to aparticular portion of the GI tract, or providing a sustained action overan extended period of time. Selectively permeable membranes surroundingan osmotically active driving compound are also suitable for orallyadministered compositions. In these latter platforms, fluid from theenvironment surrounding the capsule is imbibed by the driving compound,which swells to displace the agent or agent composition through anaperture. These delivery platforms can provide an essentially zero orderdelivery profile as opposed to the spiked profiles of immediate releaseformulations. A time-delay material such as glycerol monostearate orglycerol stearate can also be used. Oral compositions preferably includestandard excipients of pharmaceutical grade selected, for example, frommannitol, lactose, starch, magnesium stearate, sodium saccharin,cellulose, and magnesium carbonate, among others.

Controlled release oral dosage forms according to the present inventionmay also be prepared as osmotic dosage forms. The osmotic dosage formspreferably include a bilayer core comprising a drug layer (containingthe buprenorphine and/or the other opioid) and a delivery or push layer,wherein the bilayer core is surrounded by a semipermeable wall andoptionally having at least one passageway disposed therein.

The expression “passageway” as used for the purpose of this invention,includes an aperture, orifice, bore, pore, porous element, fiber,capillary tube, porous overlay, porous insert, microporous member, orporous composition through any of which the buprenorphine and/or theother opioid can diffuse, migrate or be pumped through. The passagewaycan also include a compound that erodes or is leached from the wall inthe fluid environment of use to produce at least one passageway.Representative compounds for forming a passageway include erodiblepoly(glycolic) acid or poly(lactic) acid in the wall; a gelatinousfilament; a water-removable poly(vinyl alcohol); and leachable compoundssuch as fluid-removable pore-forming polysaccharides, acids, salts oroxides. Examples of leachable compounds include sorbitol, sucrose,lactose, maltose, or fructose. The passageway can have any shape, suchas round, triangular, square and elliptical, for assisting in thecontrolled release of the buprenorphine and/or the other opioid from thedosage form. The dosage form can be manufactured with one or morepassageways in spaced-apart relation on one or more surfaces of thedosage form. A passageway and equipment for forming a passageway aredescribed in U.S. Pat. Nos. 3,845,770; 3,916,899; 4,063,064 and4,088,864. Passageways prepared by leaching are described in U.S. Pat.Nos. 4,200,098 and 4,285,987.

In certain embodiments the drug layer may comprise at least one polymerhydrogel. Examples of polymer hydrogels include but are not limited to amaltodextrin polymer; a poly(alkylene oxide) such as a poly(ethyleneoxide) and a poly(propylene oxide); an alkali carboxyalkylcellulose,wherein the alkali is sodium or potassium and the alkyl is methyl,ethyl, propyl, or butyl; and a copolymer of ethylene-acrylic acid,including methacrylic and ethacrylic acid.

In certain embodiments of the present invention, the delivery or pushlayer comprises an osmopolymer. Examples of an osmopolymer include butare not limited to a member selected from the group consisting of apolyalkylene oxide and a carboxyalkylcellulose. The polyalkylene oxidemay be a member selected from the group consisting of polymethyleneoxide, polyethylene oxide and polypropylene oxide. Thecarboxyalkylcellulose may be a member selected from the group consistingof alkali carboxyalkylcellulose, sodium carboxymethylcellulose,potassium carboxymethylcellulose, sodium carboxyethylcellulose, lithiumcarboxymethylcellulose, sodium carboxyethylcellulose,carboxyalkylhydroxyalkylcellulose, carboxymethylhydroxyethylcellulose,carboxyethylhydroxyethylcellulose andcarboxymethylhydroxypropylcellulose. The osmopolymers used for thedisplacement layer exhibit an osmotic pressure gradient across thesemipermeable wall. The osmopolymers imbibe fluid into the dosage form,thereby swelling and expanding as an osmotic hydrogel, whereby they pushthe contents of the drug layer from the osmotic dosage form.

The push layer may also include one or more osmotically effectivecompounds that imbibe an environmental fluid, for example, from thegastrointestinal tract, into the dosage form to contribute to thedelivery kinetics of the displacement layer. Examples of osmoticallyeffective compounds comprise a member selected from the group consistingof osmotic salts and osmotic carbohydrates. Examples of specificosmagents include but are not limited to sodium chloride, potassiumchloride, magnesium sulfate, lithium phosphate, lithium chloride, sodiumphosphate, potassium sulfate, sodium sulfate, potassium phosphate,glucose, fructose and maltose.

The push layer may optionally include a hydroxypropylalkylcellulose suchas hydroxypropylmethylcellulose, hydroxypropylethylcellulose,hydroxypropyl isopropyl cellulose, hydroxypropylbutylcellulose, andhydroxypropylpentylcellulose.

In certain alternative embodiments, the dosage form comprises asubstantially homogenous core comprising the buprenorphine and/or theother opioid, a pharmaceutically acceptable polymer (e.g., polyethyleneoxide) and optional excipients such as disintegrants and absorptionenhancers. The substantially homogenous core is surrounded by asemipermeable wall having a passageway (as defined above) for therelease of the buprenorphine and/or the other opioid. Such anembodiments would not require a push layer.

In certain embodiments, the semipermeable wall comprises a memberselected from the group consisting of a cellulose ester polymer, acellulose ether polymer and a cellulose ester-ether polymer.Representative wall polymers comprise a member selected from the groupconsisting of cellulose acylate, cellulose diacylate, cellulosetriacylate, cellulose acetate, cellulose diacetate, cellulosetriacetate, mono-, di- and tricellulose alkenylates, and mono-, di- andtricellulose alkinylates.

With osmotic systems, the buprenorphine or the other opioid can beformulated for controlled release and the other agent can be formulatedfor immediate release, e.g., by coating onto the semipermeable wall.

Pharmaceutical compositions of the invention include single unit dosageforms suitable for oral administration such as, but not limited to,tablets, capsules, gelcaps, and caplets, which may be adapted forcontrolled or immediate release.

In certain embodiments, both the buprenorphine and the other opioid canbe included in the same dosage form. For example, the buprenorphine andthe other opioid can both be included in a transdermal dosage form suchthat each agent is administered according to the desired rate. Incertain embodiments, the two agents can be segregated from each other ina dual reservoir system.

Transdermal Dosage Forms

In certain embodiments, wherein the buprenorphine is administered in atransdermal device, the formulation can, e.g., be a transdermal patch, atransdermal plaster, a transdermal disc or an iontophoretic transdermaldevice.

Transdermal dosage forms used in accordance with the invention caninclude a backing layer made of a pharmaceutically acceptable materialwhich is impermeable to the buprenorphine. The backing layer can serveas a protective cover for the buprenorphine and may also provide asupport function. Examples of materials suitable for making the backinglayer are films of high and low density polyethylene, polypropylene,polyvinylchloride, polyurethane, polyesters such as poly(ethylenephthalate), metal foils, metal foil laminates of suitable polymer films,textile fabrics, and the like. The backing layer can be any appropriatethickness which will provide the desired protective and supportfunctions. A suitable thickness can be, e.g., from about 10 microns toabout 200 microns.

In certain embodiments, the transdermal dosage forms used in accordancewith the invention contain a biologically acceptable polymer matrixlayer. Generally, the polymers used to form the polymer matrix layer arecapable of allowing the buprenorphine to pass through at a controlledrate. A non-limiting list of exemplary materials for inclusion in thepolymer matrix includes polyethylene, polypropylene, ethylene/propylenecopolymers, ethylene/ethylacrylate copolymers, ethylenevinyl acetatecopolymers, silicones, natural or synthetic rubber, polyacrylic estersand copolymers thereof, polyurethanes, polyisobutylene, chlorinatedpolyethylene, polyvinylchloride, vinyl chloride-vinyl acetate copolymer,polymethacrylates, polyvinylidene chloride, poly(ethyleneterephthalate), ethylene-vinyl alcohol copolymer,ethylene-vinyloxyethanol copolymer, silicones, silicone copolymers suchas polysiloxane-polymethacrylate copolymers, cellulose polymers (e.g.,ethyl cellulose, and cellulose esters), polycarbonates,polytetrafluoroethylene and mixtures thereof.

The polymer matrix layer may optionally include a pharmaceuticallyacceptable cross-linking agent such as, e.g., tetrapropoxy silane.

In certain embodiments, the transdermal delivery systems used inaccordance with the methods of the present invention include an adhesivelayer to affix the dosage form to the skin of the patient for a desiredperiod of administration, e.g., about 1 day, about 2 days, about 3 days,about 4 days, about 5 days, about 6 days, or about 7 days. If theadhesive layer of the dosage form fails to provide adhesion for thedesired period of time, it is possible to maintain contact between thedosage form with the skin, e.g., by affixing the dosage form to the skinof the patient with an adhesive tape.

The adhesive layer may include an adhesive such as polyacrylic adhesivepolymers, acrylate copolymers (e.g., polyacrylate) and polyisobutyleneadhesive polymers.

The transdermal dosage forms which can be used in accordance with thepresent invention may optionally include a permeation enhancing agent.Permeation enhancing agents are compounds which promote penetrationand/or absorption of the buprenorphine into the blood stream of thepatient. A non-limiting list of permeation enhancing agents includespolyethylene glycols, surfactants, and the like.

In one embodiment, the transdermal dosage form which may be used inaccordance with the present invention includes a non-permeable backinglayer comprising, e.g., a polyester; an adhesive layer comprising, e.g.,a polyacrylate; and a matrix containing the buprenorphine and otherexcipients such as softeners, permeability enhancers, viscosity agentsand the like.

The buprenorphine may be included in the device in a drug reservoir,drug matrix or drug/adhesive layer. Preferably, the active agent isbuprenorphine or a pharmaceutically acceptable salt thereof.

Certain preferred transdermal delivery systems also include a softeningagent. Suitable softening agents include higher alcohols such asdodecanol, undecanol, octanol, esters of carboxylic acids, diesters ofdicarboxylic acids and triglycerides. Further examples of suitablesofteners are multivalent alcohols such as levulinic acid, caprylicacids, glycerol and 1,2-propanediol, which can also be etherified by apolyethylene glycol.

A buprenorphine solvent may also be included in the transdermal deliverysystems of the present invention. A non-limiting list of suitablesolvents includes those with at least one acidic group such asmonoesters of dicarboxylic acids (e.g., monomethylglutarate andmonomethyladipate).

In certain embodiments, the transdermal dosage form includes a removableprotective layer. The removable protective layer is removed prior toapplication, and may comprise the materials used for the production ofthe backing layer disclosed above provided that they are renderedremovable, e.g., by silicone treatment. Other removable protectivelayers include polytetra-fluoroethylene, treated paper, allophane,polyvinyl chloride, and the like. Generally, the removable protectivelayer is in contact with the adhesive layer and provides a convenientmeans of maintaining the integrity of the adhesive layer until thedesired time of application.

The transdermal system utilized in the present invention is used byadhering the transdermal system to a dermal surface of a patient. Thedermal surface should be clean and unbroken. In certain embodiments, thetransdermal system will be sufficiently adhesive to remain adhered tothe patient's skin during normal everyday activities and for an adequateperiod of time. In other embodiments, it may be necessary to furthersecure the transdermal system to the patient, e.g., by wrapping tape ora medical bandage around the area to which the transdermal system hasbeen applied.

In some embodiments, the transdermal system can be cut or otherwiseseparated into two or more separate pieces to adjust the amount ofbuprenorphine that will be delivered to the patient. For example, thetransdermal system may include perforations or lines along which to cutfor dividing the transdermal system into multiple doses.

Mucosal Tablets and Films

In certain embodiments, the buprenorphine can be formulated forapplication to the mucosal tissue. Such a formulation can be a tablet,film or spray adapted for lingual (i.e., to be placed onto the tongue),sublingual (i.e., to be placed under the tongue), buccal (i.e., to beapplied to the cheek), or gingival (i.e., to be applied to the gums)administration. One benefit of such administration is the avoidance orreduction of first pass metabolism associated with oral administration.

Sublingual, lingual, buccal and gingival tablets, and films areformulated to disintegrate rapidly in the mouth to provide absorption ofthe buprenorphine in the oral cavity in a relatively short period oftime. Such forms may contain soluble excipients such as lactose,mannitol, dextrose, sucrose or mixtures thereof. Such forms may alsocontain granulating and disintegrating agents such as starch, silicondioxide, or sodium starch glycolate, binding agents such as povidone orhydroxypropyl-methyl cellulose and lubricating agents such as magnesiumstearate. Such forms may also comprise a bioerodible polymeric carrierthat optionally may also serve to adhere the dosage form to thesublingual, lingual, buccal, or gingival mucosa.

In some embodiments, the buprenorphine can be formulated as a gel in theform of a film or strip. The film should be capable of disintegratingquickly, e.g., in about 0.5 second to 120 seconds from contact with asurface in the oral cavity. In certain embodiments, the film is capableof disintegrating within about 0.5 second to about 60 seconds, or inless than about 5 seconds, or in less than about 10 seconds, or in lessthan about 15 seconds, or in less than about 20 seconds, or in less thanabout 30 seconds, or in less than about 45 seconds.

The film may comprise hydrophilic (water-soluble and water-swellable)polymers that adhere to a wet surface in the oral cavity. Polymericcarriers may be selected from acrylic acid polymers, hydrolyzedpolyvinylalcohols, polyethylene oxides, polyacrylates, vinyl polymers,polyvinylpyrrolidones, dextrans, guar gums, pectins; starches, andcellulosic polymers, among others.

Mucosal tablets or films can also include a permeation enhancer toincrease the rate at which the buprenorphine permeates through themucosal tissue to which it is applied, e.g., the buccal, lingual,gingival, or sublingual mucosa. Permeation enhancers may be selectedfrom dimethylsulfoxide (“DMSO”), dimethyl formamide (“DMF”),N,N-dimethylacetamide (“DMA”), decylmethylsulfoxide (“C₁₀MSO”),polyethylene glycol monolaurate (“PEGML”), glycerol monolaurate,lecithin, 1-substituted azacycloheptan-2-ones, alcohols, andsurfactants, among others.

The following examples are set forth to assist in understanding theinvention and should not be construed as specifically limiting theinvention described and claimed herein. Such variations of theinvention, including the substitution of all equivalents now known orlater developed, which would be within the purview of those skilled inthe art, and changes in formulation or minor changes in experimentaldesign, are to be considered to fall within the scope of the inventionincorporated herein.

EXAMPLES

In the below examples and the related graphical depictions: morphinesulphate is referred to as morphine, morphine sulphate and MS;buprenorphine free base is referred to as buprenorphine, burprenorphinefree base and bup; oxycodone hydrochloride is referred to as oxycodone,oxycodone hydrochloride and oxy.

Example 1 The Effect of Morphine Alone on GI Transit Example 1A

Test subjects: male Sprague-Dawley rats, 200-230 g; n=10/group.

Morphine sulfate (1-10 mg/kg) or 0.9% normal saline (vehicle) wasadministered subcutaneously (SC) to the test subjects. 0.5 hour later, acharcoal meal (1 ml/100 grams) was orally administered (PO) to the testsubjects.

One hour after the charcoal meal, the test subjects were euthanized byCO₂ and the gastrointestinal tract was removed from the stomach to thececum. The length of the small intestine and the distance (cm) to theleading edge of the charcoal were recorded. Data were analyzed using aone-way ANOVA followed by the Dunnett's Multiple Comparisons test where*P<0.05, **P<0.01 and***P<0.001. Data are represented as themeans±S.E.M. The results shown in FIG. 1A demonstrate that morphinedecreases gastrointestinal transit as evidenced by the decreased % ofthe small intestine traveled by a charcoal meal following morphinetreatment as compared to vehicle treated animals. This effect was dosedependent with a greater magnitude of effect observed with increasingdose.

Example 1B

Test subjects: male Sprague-Dawley rats, 200-230 g; n=10/group.

Morphine sulfate (1-10 mg/kg) or 0.9% normal saline (vehicle) wasadministered SC to the test subjects. 0.5 hour later, a charcoal meal (1ml/100 grams) was administered PO to the test subjects. One hour afterthe charcoal meal, the test subjects were euthanized by CO₂ and thestomachs were removed and weighed. Data were analyzed using a one-wayANOVA followed by the Dunnett's Multiple Comparisons test where *P<0.05,**P<0.01 and ***P<0.001. Data are represented as the means±S.E.M.Results are shown in FIG. 1B. The results shown in FIG. 1B demonstratethat morphine decreases gastrointestinal transit as evidenced byincreased stomach weight due to delayed gastric emptying. This effectwas dose dependent with a greater magnitude of effect observed withincreasing dose.

Example 2 The Effect of Morphine in Response Latency in a Rat Hot PlateAssay Example 2A

Subjects: male Sprague-Dawley rats, 200-230 g; n=10/group.

Morphine sulphate (1-10 mg/kg) was dissolved in 0.9% normal salinesolution (NSS)(vehicle) and administered SC 1 hour prior to testingagainst vehicle. Data were analyzed by a two-way ANOVA using aBonferroni Multiple Comparison Test, ***P<0.001.

The results shown in FIG. 2A demonstrate that morphine providesanalgesia as evidenced by increased latency to nocifensive response.This effect was dose dependent with a greater magnitude of effectobserved with increasing dose.

Example 2B

Subjects: male Sprague-Dawley rats, 200-230 g; n=10/group.

Morphine sulphate (1-10 mg/kg) was dissolved in 0.9% normal salinesolution (NSS)(vehicle) and administered SC 1 hour prior to testingagainst vehicle. % MPE=Percent Maximum Possible Effect. % MPE=(testlatency-baseline)/(cutoff-baseline). Data was analyzed using aBonferroni Multiple Comparison Test, ***P<0.001.

The results shown in FIG. 2 B demonstrate that morphine providesanalgesia as evidenced by increased % of the maximal possible effect (anormalized transformation of the latency to nocifensive response). Thiseffect was dose dependent with a greater magnitude of effect observedwith increasing dose.

Example 3 The Effect of Morphine in Response Latency in a Rat Tail FlickAssay Example 3A

Subjects: male Sprague-Dawley rats, 200-230 g; n=10/group.

Morphine sulphate (1-10 mg/kg) was dissolved in 0.9% normal salinesolution (NSS)(vehicle) and administered SC 1 hour prior to testingagainst vehicle. Data were analyzed by a two-way ANOVA using aBonferroni post-hoc test, *P<0.05, ***P<0.001.

The results, shown in FIG. 3A demonstrate that morphine providesanalgesia as evidenced by increased latency to nocifensive response.This effect was dose dependent with a greater magnitude of effectobserved with increasing dose.

Example 3B

Subjects: male Sprague-Dawley rats, 200-230 g; n=10/group.

Morphine sulphate (1-10 mg/kg) was dissolved in 0.9% normal salinesolution (NSS)(vehicle) and administered SC 1 hour prior to testingagainst vehicle. % MPE=Percent of Maximum Possible Effect. % MPE=(testlatency-baseline)/(cutoff(20 s)-baseline)*100. Data were analyzed by atwo-way ANOVA using a Bonferroni post-hoc test, *P<0.05, **P<0.01,***P<0.001.

The results shown in FIG. 3B demonstrate that morphine providesanalgesia as evidenced by increased % of the maximal possible effect (anormalized transformation of the latency to nocifensive response). Thiseffect was dose dependent with a greater magnitude of effect observedwith increasing dose.

Example 4 The Effect of Buprenorphine Alone on GI Transit Example 4A

Test subjects: male Sprague-Dawley rats, 220-240 g; n=10/group.

Morphine sulfate (10 mg/kg), buprenorphine free base (0.005-1 mg/kg)(Bup) or 25% hydroxylpropyl-beta-cyclodextrin (HPBCD; vehicle) wasadministered SC to test subjects. 0.5 hour later, test subjects weregiven a PO administration of a charcoal meal (1 ml/100 grams).

One hour after the charcoal meal, the test subjects were euthanized byCO₂ and the GI tract was removed from the stomach to the cecum. Thelength of the small intestine and the distance (cm) to the leading edgeof the charcoal were recorded. Data were analyzed using a one-way ANOVAfollowed by Bonferroni's Multiple Comparisons Test where *P<0.05,**P<0.01 and ****P<0.001 vs. vehicle. Data are represented as themeans+S.E.M.

The results shown in FIG. 4A demonstrates that buprenorphine decreasesgastrointestinal transit as evidenced by the decreased % of the smallintestine traveled by a charcoal meal following buprenorphine treatmentas compared to vehicle treated animals. The effect was less in magnitudeas compared to either morphine or oxycodone and a “floor effect” wasobserved such that with increasing dose further retardation of GItransit was not observed.

Example 4B

Test subjects: male Sprague-Dawley rats, 203-235 g; n=10-11/group.

Rats were dosed with buprenorphine/Bup or vehicle (25% HPBCD) PO 1 hourprior to PO administration of a charcoal meal (1 ml/100 grams), whilesome others were given 10 mg/kg of morphine sulfate 0.5 hour before thecharcoal meal. One hour after charcoal, all rats were euthanized by CO2and the GI tract was removed from the stomach to the cecum. The lengthof the small intestine and the distance (cm) to the leading edge ofcharcoal was recorded. Data were analyzed using a one-way ANOVA withBonferonni's Post-Test where ****P<0.0001 vs. vehicle. Data arerepresented as the means+S.E.M.

Results shown in FIG. 4B demonstrate that 3-100 mg/kg PO Bup alone doesnot alter GI Transit in the rat.

Example 5 The Effect of Buprenorphine in Response Latency in a Rat HotPlate Assay Example 5A

Subjects: male Sprague-Dawley rats, 225-253 g; n=10/group.

Buprenorphine free base (0.01-1 mg/kg) was formulated in 25% HPBCD(vehicle). Morphine sulphate (10 mg/kg), the positive control, wasdissolved in 0.9% NSS (vehicle). The formulations were administered SC 1hour prior to testing against vehicle. Data were analyzed by a two-wayANOVA using a Bonferroni multiple comparisons test, where *P<0.05 and***P<0.001. Data are represented as the means+S.E.M.

The results shown in FIG. 5A demonstrate that buprenorphine providesanalgesia as evidenced by increased latency to nocifensive response.This effect was dose dependent with a greater magnitude of effectobserved with increasing dose.

Example 5B

Subjects: male Sprague-Dawley rats, 225-253 g; n=10/group.

Buprenorphine free base (0.01-1 mg/kg) was formulated in 25% HPBCD(vehicle). Morphine sulphate (10 mg/kg) was dissolved in 0.9% NSS(vehicle). The formulations were administered SC 1 hour prior to testingagainst vehicle. % MPE=Percent Maximum Possible Effect. % MPE=(testlatency-baseline)/(cutoff (30 s)-baseline). Data were analyzed by atwo-way ANOVA using Bonferroni Multiple Comparisons test for post-hocanalysis, where *P<0.05 and ***P<0.001. Data are represented as themeans+SEM.

The results shown in FIG. 5B demonstrate that buprenorphine providesanalgesia as evidenced by increased % of the maximal possible effect (anormalized transformation of the latency to nocifensive response). Thiseffect was dose dependent with a greater magnitude of effect observedwith increasing dose.

Example 5C

Test Subjects: male Sprague-Dawley rats, 217-249 g; n=10-21/group.

Buprenorphine/Bup or vehicle (25% HPBCD) were administered PO 1 hourprior to testing. The positive control, morphine sulfate in 0.9% NS, wasadministered SC 1 hour prior to testing. Rats were assessed one dayprior (BL) and then 1, 3 and 5 hours post-dosing. Hot Plate was set to52° C. and cutoff was 30 seconds. Data were analyzed by a two-way ANOVAusing a Bonferroni Multiple Comparisons Test, where *P<0.05, ***P<0.001and ****P<0.0001 versus vehicle. Data are represented as the means+S.E.Mfrom two combined studies.

Results shown in FIG. 5C demonstrate that buprenorphine mitigates acutepain at MED 3 mg/kg.

Example 6 The Effect of Buprenorphine in Response Latency in a Rat TailFlick Assay Example 6A

Subjects: male Sprague-Dawley rats, 200-230 g; n=10/group

Buprenorphine free base (0.01-1 mg/kg) was formulated in 0.9% NSS(vehicle). Morphine sulphate (10 mg/kg) was dissolved in 0.9% NSS(vehicle). The formulations were administered SC 1 hour prior to testingagainst vehicle. Data were analyzed by a two-way ANOVA using aBonferroni multiple comparisons test, *P<0.05, ***P<0.001.

The results shown in FIG. 6A demonstrate that buprenorphine providesanalgesia as evidenced by increased latency to nocifensive response.This effect was dose dependent with a greater magnitude of effectobserved with increasing dose.

Example 6B

Subjects: male Sprague-Dawley rats, 200-230 g; n=10/group.

Buprenorphine free base (0.01-1 mg/kg) was formulated in 25% HPBCD(vehicle). Morphine sulphate (10 mg/kg) was dissolved in 0.9% NSS(vehicle). The formulations were administered SC 1 hour prior to testingagainst vehicle. % MPE=Percent Maximum Possible Effect. % MPE=(testlatency-baseline)/(cutoff(20 s)-baseline)*100. Data were analyzed by atwo-way ANOVA using a Bonferroni multiple comparisons test, ***P<0.001.

The results shown in FIG. 6B demonstrate that buprenorphine % of themaximal possible effect (a normalized transformation of the latency tonocifensive response). This effect was dose dependent with a greatermagnitude of effect observed with increasing dose.

Example 6C

Test subjects: male Sprague-Dawley rats, 217-261 g; n=10-21/group.

Buprenorphine base/Bup or vehicle (25% HPBCD) were administered PO 1hour prior to testing. The positive control, morphine sulfate in 0.9% NSwas administered SC 1 hour prior to testing. Rats were assessed the dayprior (BL) and then 1, 3 and 5 hours post-dosing. Tail Flick was set to40 intensity and cutoff 20 seconds. Data were analyzed by a two-wayANOVA using a Bonferroni Multiple Comparisons Test, where*P<0.05,***P<0.001 and ****P<0.0001. Data are represented as themeans+S.E.M of two combined studies.

Results shown in FIG. 6C demonstrate that buprenorphine mitigates acutepain at MED≦1 mg/kg PO.

Example 7 The Effect of Oxycodone on GI Transit Example 7A

Subjects: male Sprague-Dawley rats, 207-255 g; n=10/group.

Morphine sulfate (10 mg/kg), oxycodone hydrochloride (0.3-5 mg/kg), orsaline (vehicle) were administered SC 0.5 hour (morphine) or 1 hour(oxycodone, vehicle) prior to the PO administration of a charcoal meal(1 ml/100 grams). One hour later, the rats were euthanized by CO₂ andthe gastrointestinal tract was removed from the stomach to the cecum.The length of the small intestine and the distance (cm) to the leadingedge of charcoal were recorded. Data were analyzed using a one-way ANOVAfollowed by the Dunnett's Multiple Comparisons test where ***P<0.001.Data are represented as the mean+S.E.M.

The results shown in FIG. 7A demonstrate that oxycodone decreasesgastrointestinal transit as evidenced by the decreased % of the smallintestine traveled by a charcoal meal following oxycodone treatment ascompared to vehicle treated animals. This effect was dose dependent witha greater magnitude of effect observed with increasing dose.

Example 7B

Test subjects: male Sprague-Dawley rats, 207-255 g; n=10/group.

Morphine sulfate, the positive control, oxycodone HCl, or saline(vehicle) were administered SC either 0.5 hr (morphine) or 1 hour(oxycodone, vehicle) prior to the PO administration of a charcoal meal(1 ml/100 grams). One hour later, rats were euthanized by CO2 and the GItract was removed from the stomach to the cecum. The length of the smallintestine and the distance (cm) to the leading edge of charcoal wasrecorded. Data were analyzed using a one-way ANOVA followed by theDunnett's Multiple Comparisons test where ***P<0.001. Data arerepresented as the mean+S.E.M.

The results are shown in FIG. 7B.

Example 7C

Test subjects: male Sprague-Dawley rats, 225-255 g; n=10/group.

Oxycodone HCl, or water (vehicle) were administered PO, while morphinesulfate, the positive control, was administered SC, either 0.5 hr(morphine) or 1 hour (oxycodone HCl, vehicle) prior to the POadministration of a charcoal meal (1 ml/100 grams). One hour later, ratswere euthanized by CO2 and the GI tract was removed from the stomach tothe cecum. The length of the small intestine and the distance (cm) tothe leading edge of charcoal was recorded. Data were analyzed using aone-way ANOVA followed by the Dunnett's Multiple Comparisons test where**P<0.01 and ***P<0.001. Data are represented as the mean+S.E.M.

The results are shown in FIG. 7C.

Example 7D

Test subjects: male Sprague-Dawley rats, 197-252 g on the day oftesting; n=9-11/group.

Rats were dosed with Oxycodone HCl/Oxy or vehicle (water) PO once dailyfor 5 days (chronic). Additional groups were dosed only once on day 5(acute). One hour after the oxy dosing, a PO administration of acharcoal meal (1 ml/100 grams) was given. One hour after charcoal, allrats were euthanized by CO2 and the GI tract was removed from thestomach to the cecum. The length of the small intestine and the distance(cm) to the leading edge of charcoal was recorded. Data were analyzedusing a one-way ANOVA with Bonferonni's Multiple Comparison Test where*P<0.05, ****P<0.0001 vs. vehicle (chronic), ### vs. oxycodone (acute).Data are represented as the means+S.E.M.

The results shown in FIG. 7D demonstrate that repeated oxycodone dosingproduces some tolerances to its acute effect on the inhibition of GItransit.

Example 8 The Effect of Oxycodone in Response Latency in a Rat Hot PlateAssay Example 8A

Subjects: male Sprague-Dawley rats, 234-279 g; n=10/group.

Oxycodone hydrochloride (0.3-5 mg/kg) was dissolved in 0.9% normalsaline solution (NSS)(vehicle) and administered SC 1 hour prior totesting against vehicle. Hot plate was set to 52° C. and cutoff was 30seconds. Data were analyzed by a two-way ANOVA using a Bonferronimultiple comparisons test, where ****P<0.0001. Data are represented asthe means+S.E.M.

The results shown in FIG. 8A demonstrate that oxycodone providesanalgesia as evidenced by increased latency to nocifensive response.This effect was dose dependent with a greater magnitude of effectobserved with increasing dose.

Example 8B

Subjects: male Sprague-Dawley rats, 234-279 g; n=10/group. Compound wasadministered SC 1 hour prior to testing. Oxycodone hydrochloride (0.3-5mg/kg) was dissolved in 0.9% normal saline solution (NSS)(vehicle) andadministered SC 1 hour prior to testing against vehicle. Hot plate wasset to 52° C. and cutoff was 30 seconds. % MPE=. Percent MaximumPossible Effect. % MPE=(test latency-baseline)/(cutoff (30 s)-baseline).Data were analyzed by a two-way ANOVA using Bonferroni MultipleComparisons test for post-hoc analysis, ****P<0.000. Data arerepresented as the means+SEM.

The results shown in FIG. 8B demonstrate that oxycodone providesanalgesia as evidenced by increased % of the maximal possible effect (anormalized transformation of the latency to nocifensive response). Thiseffect was dose dependent with a greater magnitude of effect observedwith increasing dose.

Example 8C

Test subjects: male Sprague-Dawley rats, 200-230 g; n=10/group

Oxycodone HCl was administered SC 1 hour prior to testing. Thermallatency was assessed the day prior (BL) and then 1, 3 and 5 hourspost-oxycodone dosing. The hotplate was set to 52° C. and the cutoff was30 seconds. Oxycodone was dissolved in 0.9% NS (vehicle). Note: at 10mg/kg, 4 out of 10 were found dead at the 3 hr time point. Data wereanalyzed by a two-way ANOVA using the Bonferroni Multiple Comparisonstest for post-hoc analysis where, ***P<0.001. Data are represented asthe means+SEM.

The results shown in FIG. 8C demonstrate that oxycodone mitigates acutepain in the rat; MED=3 mg/kg SC.

Example 8D

Subjects: male Sprague-Dawley rats, 226-251 g; n=10/group.

Oxycodone HCl was administered PO 1 hour prior to testing, whilemorphine sulfate, the positive control, was administered SC 1 hour priorto testing. Behavior was assessed the day prior (BL) and then 1, 3, 5and 24 hours post-compound administration. The hot plate was set to 52°C. and the cutoff was 30 seconds. Oxycodone was dissolved in water(vehicle), while morphine sulfate was dissolved in 0.9% NS. Data wereanalyzed by a two-way ANOVA using a Bonferroni Multiple ComparisonsTest, where ****P<0.0001.

The results shown in FIG. 8D demonstrate that oxycodone mitigates acutepain in the rat; MED=10 mg/kg PO.

Example 9 The Effect of Oxycodone in Response Latency in a Rat TailFlick Assay Example 9A

Subjects: male Sprague-Dawley rats, 234-279 g; n=10/group.

Oxycodone hydrochloride (0.3-5 mg/kg) was dissolved in 0.9% normalsaline solution (NSS)(vehicle) and administered SC 1 hour prior totesting against vehicle. Data were analyzed by a two-way ANOVA using aBonferroni multiple comparisons test, ****P<0.001.

The results shown in FIG. 9A demonstrate that oxycodone providesanalgesia as evidenced by increased latency to nocifensive response.This effect was dose dependent with a greater magnitude of effectobserved with increasing dose.

Example 9B

Subjects: male Sprague-Dawley rats, 234-279 g; n=10/group.

Oxycodone hydrochloride (0.3-5 mg/kg) was dissolved in 0.9% normalsaline solution (NSS)(vehicle) and administered SC 1 hour prior totesting against vehicle. % MPE=Percent Maximum Possible Effect. %MPE=(test latency-baseline)/(cutoff(20 s)-baseline)*100. Data wereanalyzed by a two-way ANOVA using a Bonferroni multiple comparisonstest, ****P<0.001.

The results shown in FIG. 9B demonstrate that oxycodone providesanalgesia as evidenced by increased % of the maximal possible effect (anormalized transformation of the latency to nocifensive response). Thiseffect was dose dependent with a greater magnitude of effect observedwith increasing dose.

Example 9C

Test subjects: male Sprague-Dawley rats, 200-230 g; n=10/group.

Oxycodone HCl and vehicle were administered SC 1 hour prior to testing.Rats were assessed one day prior (BL) and then 1, 3 and 5 hourspost-oxycodone administration. The tail flick was set to an intensity of40 and the cutoff was 20 seconds. Oxycodone was dissolved in 0.9%(vehicle). Note: for the 10 mg/kg dosing group, 4 out of 10 rats werefound dead at the 3 hr time point. Data were analyzed by a two-way ANOVAfollowed by the Bonferroni Multiple Comparisons Test where, *P<0.05 and****P<0.001.

The results shown in FIG. 9C demonstrate that oxycodone mitigates acutepain in the rat, MED=3 mg/kg SC.

Example 9D

Test subjects: male Sprague-Dawley rats, 226-251 g; n=10/group.

Oxycodone HCl was administered PO 1 hour prior to testing, whilemorphine sulfate, the positive control, was administered SC 1 Hour priorto testing. Behavior was assessed the day prior (BL) to dosing, and then1, 3, 5 and 24 hours post-compound administration. The tail flick wasset to an intensity of 40 and 20 seconds was used as the cutoff.Oxycodone was dissolved in water (vehicle), while morphine was dissolvedin 0.9% NS. Data were analyzed by a two-way ANOVA using a BonferroniMultiple Comparisons Test, where *P<0.05, **P<0.01, ***P<0.001 and****P<0.0001.

The results shown in FIG. 9D demonstrate that oxycodone mitigates acutepain in the rat; MED=10 mg/kg PO.

Example 10 The Effect of Buprenorphine on Morphine-Induced Inhibition ofGI Transit

Test subjects: male Sprague-Dawley rats, 220-240 g; n=8-21/group.

Buprenorphine free base (0.0005-1 mg/kg) (Bup) or 25%hydroxylpropyl-beta-cyclodextrin (HPBCD; vehicle) was administered SC tothe test subjects. 1 hour later, a SC dose of 10 mg/kg morphine sulfateor saline was administered. 0.5 hour after morphine or saline injection,the test subjects were given a PO administration of a charcoal meal (1ml/100 grams).

One hour after the charcoal meal, the test subjects were euthanized byCO₂ and the GI tract was removed from the stomach to the cecum. Thelength of the small intestine and the distance (cm) to the leading edgeof the charcoal were recorded. Data were analyzed using a one-way ANOVAwith Bonferroni's multiple comparisons test. *P<0.05, ***P<0.001 vs.vehicle/saline and ###P<0.001 vs. vehicle/morphine. Data are representedas the means±S.E.M. The results shown in FIG. 10 demonstrate thatbuprenorphine when administered prior to morphine prevents the morphineinduced retardation of GI transit. This effect was dose dependent with agreater magnitude of effect observed with increasing dose.

Example 11 The Effect of Buprenorphine on Morphine Co-Administration onRat GI Transit

Test subjects: male Sprague-Dawley rats, 226-260 g; n=10/group.

Buprenorphine free base (0.0005-1 mg/kg) (Bup) or 25%hydroxylpropyl-beta-cyclodextrin (HPBCD; vehicle) was administered SC tothe test subjects immediately prior to a SC dose of 10 mg/kg morphinesulfate or saline (co-administration; different sites). 0.5 hour aftermorphine injection, the test subjects were given a PO administration ofa charcoal meal (1 ml/100 grams).

One hour after the charcoal meal, the test subjects were euthanized byCO₂ and the GI tract was removed from the stomach to the cecum. Thelength of the small intestine and the distance (cm) to the leading edgeof the charcoal were recorded. Data were analyzed using a one-way ANOVAwith Bonferroni's multiple comparisons test. *P<0.05, ****P<0.0001 vs.vehicle/saline and ####P<0.0001 vs. vehicle/morphine. Data arerepresented as the means±S.E.M. The results shown in FIG. 11 demonstratethat buprenorphine when co-administered with morphine prevents themorphine induced retardation of GI transit. This effect was dosedependent with a greater magnitude of effect observed with increasingdose.

Example 12 The Effect of Buprenorphine and Morphine in Response Latencyin a Rat Hot Plate Assay Example 12A

Subjects: male Sprague-Dawley rats, 220-243 g; n=10/group.

Buprenorphine free base (0.005-1 mg/kg) was formulated in 25% HPBCD(vehicle) while morphine sulphate (10 mg/kg), the positive control, wasdissolved in 0.9% NSS (vehicle). Buprenorphine free base (0.005-1 mg/kg)was administered SC 1 hour prior to morphine sulfate (10 mg/kg). Ratswere assessed for thermal latency the day prior to dosing, then 1.5, 3and 5 hours post-morphine administration. Data were analyzed by atwo-way ANOVA using the Bonferroni Multiple Comparisons Test, where****P<0.0001 compared to vehicle+vehicle. Data are represented as themeans+S.E.M.

The results shown in FIG. 12A demonstrate that buprenorphine whenadministered prior to morphine produces some erosion of the analgesicefficacy of morphine, as evidenced by a statistically significantreduction in latency to nocifensive response as compared to morphinealone. This effect was dose dependent with a greater magnitude of effectobserved with increasing dose.

Example 12B

Subjects: male Sprague-Dawley rats, 220-243 g; n=10/group.

Buprenorphine free base (0.005-1 mg/kg) was formulated in 25% HPBCD(vehicle) while morphine sulphate (10 mg/kg), the positive control, wasdissolved in 0.9% NSS (vehicle). Buprenorphine free base (0.005-1mg/kg), was administered SC 1 hour prior to morphine sulfate (10 mg/kg).Rats were assessed for thermal latency 1.5, 3 and 5 hours post-morphineadministration. % MPE=Percent Maximum Possible Effect. % MPE=(testlatency-baseline)/(cutoff (30 s)-baseline). Data were analyzed by atwo-way ANOVA using Bonferroni Multiple Comparisons test for post-hocanalysis, where **P<0.01 and ****P<0.0001. Data are represented as themeans+SEM.

The results shown in FIG. 12B demonstrate that buprenorphineadministered prior to morphine produces some erosion of the analgesicefficacy of morphine, as evidenced by a statistically significantreduction in the % of the maximum possible effect (a normalizedtransformation of the latency to nocifensive response) as compared tomorphine alone. This effect was dose dependent with a greater magnitudeof effect observed with increasing dose.

Example 13 The Effect of Buprenorphine and Morphine in Response Latencyin a Rat Tail Flick Assay Example 13A

Subjects: male Sprague-Dawley rats, 198-243 g; n=10/group.

Buprenorphine free base (0.005-1 mg/kg) was formulated in 25% HPBCD(vehicle) while morphine sulphate (10 mg/kg), the positive control, wasdissolved in 0.9% NSS (vehicle). Buprenorphine free base (0.005-1mg/kg), was administered SC 1 hour prior to, morphine sulfate (10mg/kg). Rats were assessed for tail flick latency the day prior todosing, then 1.5, 3 and 5 hours post-morphine administration. Data wereanalyzed by a two-way ANOVA using the Bonferroni Multiple ComparisonsTest, where ****P<0.0001 compared to vehicle+vehicle. Data arerepresented as the means+S.E.M.

The results shown in FIG. 13A demonstrate that buprenorphine whenadministered prior to morphine produces some erosion of the analgesicefficacy of morphine, as evidenced by a statistically significantreduction in latency to nocifensive response as compared to morphinealone. This effect was dose dependent with a greater magnitude of effectobserved with increasing dose.

Example 13B

Subjects: male Sprague-Dawley rats, 198-243 g; n=10/group.

Buprenorphine free base (0.005-1 mg/kg) was formulated in 25% HPBCD(vehicle) while morphine sulphate (10 mg/kg), the positive control, wasdissolved in 0.9% NSS (vehicle). Buprenorphine free base (0.005-1mg/kg), was administered SC 1 hour prior to morphine sulfate (10 mg/kg).Rats were assessed for thermal latency 1.5, 3 and 5 hours post-morphineadministration. % MPE=Percent Maximum Possible Effect. % MPE=(testlatency-baseline)/(cutoff(20 s)-baseline)*100. Data were analyzed by atwo-way ANOVA using a Bonferroni multiple comparisons test for post-hocanalysis where *P<0.05 and ****P<0.001. Data are represented as themeans+SEM.

The results shown in FIG. 13B demonstrate that buprenorphineadministered prior to morphine produces some erosion of the analgesicefficacy of morphine, as evidenced by a statistically significantreduction in the % of the maximum possible effect (a normalizedtransformation of the latency to nocifensive response) as compared tomorphine alone. This effect was dose dependent with a greater magnitudeof effect observed with increasing dose.

Example 14 The Effect of Buprenorphine and Oxycodone on GI TransitExample 14A

Subjects: male Sprague-Dawley rats, 211-236 g; n=10/group.

Rats were dosed with buprenorphine free base (0.005-0.5 mg/kg) orvehicle (25% HPBCD) SC 1 hour prior to an SC dose of 8 mg/kg oxycodonehydrochloride, 10 mg/kg morphine sulphate, or vehicle (0.9% saline). 0.5hr (in the case of morphine) or 1 hour (other treatments) later the ratsreceived PO administration of a charcoal meal (1 ml/100 grams). One hourafter charcoal administration, all rats were euthanized by CO₂ and theGI tract was removed from the stomach to the cecum. The length of thesmall intestine and the distance (cm) to the leading edge of charcoalwere recorded. Data were analyzed using a one-way ANOVA withBonferonni's Post-Test where **P<0.01, ****P<0.0001 vs. vehicle and####P<0.0001 vs. vehicle+oxycodone. Data are represented as themeans+S.E.M.

The results shown in FIG. 14A demonstrate that buprenorphine whenadministered prior to oxycodone prevents the oxycodone inducedretardation of GI transit. This effect was dose dependent with a greatermagnitude of effect observed with increasing dose. Buprenorphinedisplays a higher potency (i.e. significant effects observed at lowerdoses) against oxycodone induced retardation of GI transit as comparedto morphine induced retardation of GI transit.

Example 14B

Subjects: male Sprague-Dawley rats, 211-236 g; n=10/group.

Rats were dosed with buprenorphine free base (0.5-3) or vehicle (25%HPBCD) SC 1 hour prior to an SC dose of 8 mg/kg oxycodone hydrochloride,10 mg/kg morphine sulphate, or vehicle (0.9% saline). 0.5 hr (in thecase of morphine) or 1 hour (other treatments) later the rats receivedPO administration of a charcoal meal (1 ml/100 grams). One hour aftercharcoal administration, all rats were euthanized by CO₂ and the GItract was removed from the stomach to the cecum. The length of the smallintestine and the distance (cm) to the leading edge of charcoal wererecorded. Data were analyzed using a one-way ANOVA with Bonferonni'sPost-Test where **P<0.01, ****P<0.0001 vs. vehicle and ####P<0.0001 vs.vehicle+oxy. Data are represented as the means+S.E.M.

The results shown in FIG. 14B demonstrate that buprenorphine whenadministered prior to oxycodone prevents the oxycodone inducedretardation of GI transit. A “ceiling effect” was observed wherebyincreasing doses of buprenorphine did not produce greater magnitude ofeffects.

Example 15 The Effect of PO Buprenorphine on Oxycodone-InducedInhibition on Rat GI Transit

Test subjects: male Sprague-Dawley rats, 224-253 g; n=10 or 11/group.

Buprenorphine free base (30-300 mg/kg) (Bup) or 25%hydroxylpropyl-beta-cyclodextrin (HPBCD; vehicle) was orallyadministered to the test subjects one hour prior to an oraladministration of 100 mg/kg oxycodone or water. One hour after the oraloxycodone administration, the test subjects were given a POadministration of a charcoal meal (1 ml/100 grams).

One hour after the charcoal meal, the test subjects were euthanized byCO₂ and the GI tract was removed from the stomach to the cecum. Thelength of the small intestine and the distance (cm) to the leading edgeof the charcoal were recorded. Data were analyzed using a one-way ANOVAwith Bonferroni's Post-Test where *P<0.05, **P<0.01, ***P<0.001 and****P<0.0001 vs. veh+veh, and ####P<0.0001 vs. veh+oxycodone. Data arerepresented as the means+S.E.M.

The results are shown in FIG. 15.

Example 16 The Effect of Oral PO Buprenorphine and Oral Oxycodone Dosingon Rat GI Transit

Test subjects: male Sprague-Dawley rats, 226-265 g; n=10/group.

Buprenorphine free base (3-30 mg/kg) (Bup) or 25%hydroxylpropyl-beta-cyclodextrin (HPBCD; vehicle) was orallyadministered to the test subjects one hour prior to an oraladministration of 100 mg/kg oxycodone or water. One hour after the oraloxycodone administration, the test subjects were given a POadministration of a charcoal meal (1 ml/100 grams).

One hour after the charcoal meal, the test subjects were euthanized byCO₂ and the GI tract was removed from the stomach to the cecum. Thelength of the small intestine and the distance (cm) to the leading edgeof the charcoal were recorded. Data were analyzed using a one-way ANOVAwith Bonferroni's Post-Test where * P<0.05, **P<0.01, ****P<0.0001 vs.vehicle+vehicle and #P<0.05 vs. veh+Oxy. Data are represented as themeans+S.E.M.

The results are shown in FIG. 16.

Example 17 The Effect of Buprenorphine and Oxycodone in Response Latencyin a Rat Hot Plate Assay Example 17A

Subjects: male Sprague-Dawley rats, 227-252 g; n=10/group.

Buprenorphine free base (0.005-1 mg/kg) or vehicle (25% HPBCD) wereadministered SC 1 hour prior to a SC injection of 8 mg/kg oxycodone orvehicle (0.9% saline). Rats were tested 1 hour after oxycodoneinjection. Hot plate was set to 52° C. and cutoff was 30 seconds. Datawere analyzed by a two-way ANOVA using a Bonferroni multiple comparisonstest, where ####P<0.0001 vs. veh+oxy. All oxy-dosed groups weresignificantly different from vehicle+vehicle at 1 hour (P<0.0001) and*P<0.05 at 3 hours. Data are represented as the means+S.E.M

The results shown in FIG. 17A demonstrate that buprenorphine whenadministered prior to oxycodone does not produces erosion of theanalgesic efficacy of oxycodone, as evidenced by a lack of statisticallysignificant reduction in latency to nocifensive response as compared tooxycodone alone. Importantly the same dose range was effective inprevention of oxycodone induced retardation of GI transit.

Example 17B

Subjects: male Sprague-Dawley rats, 227-252 g; n=10/group.

Buprenorphine free base (0.005-0.5 mg/kg) or vehicle (25% HPBCD) wereadministered SC 1 hour prior to a SC injection of oxycodone or vehicle(0.9% saline). Rats were tested 1 hour after oxycodone injection. Hotplate was set to 52° C. and cutoff was 30 seconds.

% MPE=Percent Maximum Possible Effect. % MPE=(testlatency-baseline)/(cutoff (30 s)-baseline). Data were analyzed by atwo-way ANOVA using a Bonferroni multiple comparisons test, where####P<0.0001 vs. vehicle+oxycodone. ****<P 0.0001 significantlydifferent from veh+veh at 1 hour (P<0.0001). Data are represented as themeans+S.E.M.

The results shown in FIG. 17B demonstrate that buprenorphine whenadministered prior to oxycodone does not produces erosion of theanalgesic efficacy of oxycodone, as evidenced by a lack of statisticallysignificant reduction in the % of the maximum possible effect (anormalized transformation of the latency to nocifensive response) ascompared to oxycodone alone. Importantly the same dose range waseffective in prevention of oxycodone induced retardation of GI transit.

Example 18 The Effect of Buprenorphine and Oxycodone in Response Latencyin a Tail Flick Assay Example 18A

Subjects: male Sprague-Dawley rats, 209-242 g; n=10/group.

Buprenorphine free base (0.005-0.5 mg/kg) or vehicle (25% HPBCD) wereadministered SC 1 hour prior to a SC injection of 8 mg/kg oxycodone orvehicle (0.9% saline). Rats were tested 1 hour after oxycodoneinjection. Tail Flick was set to 40 Intensity and cutoff was 20 seconds.Data were analyzed by a two-way ANOVA using a Bonferroni multiplecomparisons test, where ##P<0.0001 vs. veh+oxy. ****P<0.0001 weresignificantly different from vehicle+vehicle at 1 hour. Data arerepresented as the means+S.E.M.

The results shown in FIG. 18A demonstrate that buprenorphine whenadministered prior to oxycodone does not produces erosion of theanalgesic efficacy of oxycodone, as evidenced by a lack of statisticallysignificant reduction in latency to nocifensive response as compared tooxycodone alone. Importantly the same dose range was effective inprevention of oxycodone induced retardation of GI transit.

Example 18B

Subjects: male Sprague-Dawley rats, 227-252 g; n=10/group.

Buprenorphine free base (0.005-0.5 mg/kg) or vehicle (25% HPBCD) wereadministered SC 1 hour prior to a SC injection of oxycodone or vehicle(0.9% saline). Rats were tested 1 hour after oxycodone injection. TailFlick was set to 40 Intensity and cutoff was 20 seconds.

% MPE=Percent Maximum Possible Effect. % MPE=(testlatency-baseline)/(cutoff (30 s)-baseline). Data were analyzed by atwo-way ANOVA using a Bonferroni multiple comparisons test, where#P<0.05 vs. vehicle+oxycodone and ****P,0.0001 vs. vehicle+vehicle. Dataare represented as the means+S.E.M.

The results shown in FIG. 18B demonstrate that buprenorphine whenadministered prior to oxycodone does not produces erosion of theanalgesic efficacy of oxycodone, as evidenced by a lack of statisticallysignificant reduction in the % of the maximum possible effect (anormalized transformation of the latency to nocifensive response) ascompared to oxycodone alone. Importantly the same dose range waseffective in prevention of oxycodone induced retardation of GI transit.

Example 19 The Effect of Buprenorphine and Oxycodone Co-Administrationon Acute Analgesia Example 19A

Test subjects: Male Sprague-Dawley rats, 209-242 g, n=10/group

Oxycodone HCl (8 mg/kg), buprenorphine free base (0.005 mg/kg-0.5mg/kg)(Bup) or 25% hydroxylpropyl-beta-cyclodextrin/saline(HPBCD/saline; vehicle) were co-administered subcutaneously (SC) albeitat different sites. Rats were assessed one day prior (BL) and then 1, 3,and 5 hours post co-administration. Tail Flick was set to 40 Intensityand cutoff was 20 seconds. Data was analyzed by a two-way ANOVA using aBonferroni multiple comparisons test, where all groups weresignificantly different from veh+veh at 1 hour, ****P<0.0001. Data arerepresented as the means+S.E.M.

The results shown in FIG. 19A demonstrate that buprenorphinepretreatment does not attenuate the analgesic effect of 8 mg/kgoxycodone.

Example 19B

Oxycodone HCl (8 mg/kg), buprenorphine free base (0.005 mg/kg-0.5mg/kg)(Bup) or 25% hydroxylpropyl-beta-cyclodextrin/saline(HPBCD/saline; vehicle) were co-administered subcutaneously (SC) albeitat different sites. Rats were assessed one day prior (BL) and then 1, 3,and 5 hours post co-administration. Hot plate was set to 52° C. andcutoff was 30 seconds. Data was analyzed by a two-way ANOVA using aBonferroni multiple comparisons test, where all groups weresignificantly different from veh+veh at 1 hour, ****P<0.0001 and####P<0.0001 and ###P<0.001 vs. veh+8 mg/kg Oxycodone. Data arerepresented as the means+S.E.M.

The results shown in FIG. 19B demonstrate that buprenorphinepretreatment does not attenuate the analgesic effect of 8 mg/kgoxycodone.

Example 20 The Effect of Buprenorphine Pretreatment on Oxycodone-InducedInhibition of GI Transit in the Rat

Test subjects: Male Sprague-Dawley rats, 211-236 g, n=10-20/group

Rats were dosed with buprenorphine free base (0.005 mg/kg-3 mg/kg)(Bup)or 25% hydroxylpropyl-beta-cyclodextrin (HPBCD vehicle), 10 mg/kgmorphine, or vehicle (0.9% saline), ½ hour (in the case of morphine) or1 hour (all other treatments) later, the rats received a charcoal mealPO (1 ml/100 g). One hour after charcoal, all rats were euthanized byCO2 and the GI tract was removed from the stomach to the cecum. Thelength of the small intestine and the distance (cm) to the leading edgeof charcoal was recorded. Data were analyzed using a one-way ANOVA withBonferroni Post-Test, where **P<0.01, ****P<0.0001 vs. veh+veh, and####P<0.0001 vs. veh+oxycodone. Data are represented as the means+S.E.M.

The results shown in FIG. 20 demonstrate that 0.05 mg/kg SCbuprenorphine attenuates the constipating effect of SC oxycodone.

Example 21 The Effect of Buprenorphine+Oxycodone SC Co-Administration onGI Transit in the Rat

Test subjects: Male Sprague-Dawley rats, 211-236 g, n=10-20/group

Oxycodone or vehicle (25% HPBCD) were administered SC immediately priorto SC buprenorphine; BUP or saline (co-admin; different sites). One hourlater, rats were given a PO administration of a charcoal meal (1 ml/100grams). One hour after charcoal, all rats were euthanized by CO2 and theGI tract was removed from the stomach to the cecum. The length of thesmall intestine and the distance (cm) to the leading edge of charcoalwere recorded. Subjects: male Sprague-Dawley rats, 226-258 g;n=10/group. Data were analyzed using a one-way ANOVA with Bonferonni'sPost-Test where ***P<0.001, and ****P<0.0001 vs. veh+veh and ###P<0.001,####P<0.0001 vs. veh+oxycodone. Data are represented as the means+S.E.M.

The results shown in FIG. 21 demonstrate that when co-Administered,0.005 mg/kg SC buprenorphine can attenuate the constipating effect of SCoxycodone.

Example 22 The Summarized Effect of Buprenorphine PO Pre-Treatment onOxycodone-Induced Inhibition of GI Transit in the Rat

Test subjects: male Sprague-Dawley rats, 223-250 g; n=10-41/group (4studies combined).

Rats were dosed PO with Buprenorphine/Bup or vehicle (25% HPBCD) PO. Onehour later they were dosed PO with Oxycodone/Oxy or vehicle (water). Onehour after Oxy or veh, a PO administration of a charcoal meal (1 ml/100grams) was given. One hour after charcoal, all rats were euthanized byCO2 and the GI tract was removed from the stomach to the cecum. Thelength of the small intestine and the distance (cm) to the leading edgeof charcoal was recorded. Data were analyzed using a one-way ANOVA withBonferonni's Multiple Comparison Test, where *P<0.05, **P<0.01,***P<0.001 vs. vehicle+vehicle and #P<0.05, ##P<0.01, ###P<0.001,####P<0.0001 vs. vehicle+100 mg/kg oxycodone. Data are represented asthe means+S.E.M.

The results shown in FIG. 22 demonstrate that 3 mg/kg is the lowest POdose that attenuates the constipating effect of oral oxycodone (combineddata sets).

Example 23 The Effect of a Single Bup Administration onOxycodone-Induced Attenuation of GI Transit in the Rat FollowingRepeated Oxycodone Dosing

Test subjects: male Sprague-Dawley rats, 203-253 g on the day oftesting; n=9-0/group.

Rats were dosed once daily for 5 days with Oxycodone/Oxy or saline SC.On the 5th day, Buprenorphine/Bup or vehicle (25% HPBCD) wasadministered SC at the same time as the last oxycodone dose. One hourlater, a PO administration of a charcoal meal (1 ml/100 grams) wasgiven. One hour after charcoal, all rats were euthanized by CO2 and theGI tract was removed from the stomach to the cecum. The length of thesmall intestine and the distance (cm) to the leading edge of charcoalwas recorded. Data were analyzed using a one-way ANOVA with Bonferonni'sMultiple Comparisons Test where **P<0.01, ****P<0.0001 vs.vehicle+vehicle and #P<0.05 vs. veh+Oxy. Data are represented as themeans+S.E.M.

The results shown in FIG. 23 demonstrate that acute 0.5 mg/kg SCbuprenorphine administration reverses oxycodone-induced inhibition of GITransit.

Example 24 The Effect of Repeated Buprenorphine and Oxycodone SCAdministration (Co-Administration) on GI Transit in the Rat

Test subjects: male Sprague-Dawley rats, 202-250 g on the day oftesting; n=9-11/group.

Rats were co-dosed for 5 days with Oxycodone/Oxy or water andBuprenorphine/Bup or vehicle (25% HPBCD) SC. One hour after the 5th doseof each, a PO administration of a charcoal meal (1 ml/100 grams) wasgiven. One hour after charcoal, all rats were euthanized by CO2 and theGI tract was removed from the stomach to the cecum. The length of thesmall intestine and the distance (cm) to the leading edge of charcoalwas recorded. Data were analyzed using a one-way ANOVA with Bonferonni'sMultiple Comparison Test where **P<0.01, ****P<0.0001 vs.vehicle+vehicle and #P<0.05, ####P<0.0001 vs. veh+Oxy. Data arerepresented as the means+S.E.M.

The results shown in FIG. 24 demonstrate that repeated dosing with SCbuprenorphine×5 days lowers the MED needed to attenuate the effect ofoxycodone on GI Transit (0.05 mg vs. 0.5 mg/kg).

The present invention is not to be limited in scope by the specificembodiments disclosed in the examples which are intended asillustrations of a few aspects of the invention and any embodiments thatare functionally equivalent are within the scope of this invention.Indeed, various modifications of the invention in addition to thoseshown and described herein will become apparent to those skilled in theart and are intended to fall within the scope of the appended claims.

1-103. (canceled)
 104. A composition comprising an opioid analgesic and an effective amount of buprenorphine to prevent or treat an adverse pharmacodynamic response induced by the administration of the opioid 